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Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019

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Introduction, deaths in which infection played a role, infectious syndrome estimates, pathogen distribution, estimating mortality and ylls, uncertainty and validity analysis, role of the funding source.

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Declaration of interests, acknowledgments, supplementary materials (2), related hub.

Global Burden of Disease The Global Burden of Disease study provides the most comprehensive global health estimates, examining worldwide, national, and regional trends for mortality and morbidity from major diseases, injuries, and risk factors to understand the health challenges of the 21st century.

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Review article impact of climate change on human infectious diseases: empirical evidence and human adaptation.

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Emerging infectious diseases never end: The fight continues

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• 1 National Clinical Research Center for Infectious Diseases, State Key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Second Hospital Affiliated with the Southern University of Science and Technology, Shenzhen, China.
• PMID: 37331800
• DOI: 10.5582/bst.2023.01104

Emerging infectious diseases have accompanied the development of human society while causing great harm to humans, and SARS-CoV-2 was only one in the long list of microbial threats. Many viruses have existed in their natural reservoirs for a very long time, and the spillover of viruses from natural hosts to humans via interspecies transmission serves as the main source of emerging infectious diseases. Widely existing viruses capable of utilizing human receptors to infect human cells in animals signal the possible outbreak of another viral infection in the near future. Extensive and close collaborative surveillance across nations, more effective wildlife trade legislation, and robust investment into applied and basic research will help to combat the possible pandemics of new emerging infectious diseases in the future.

Keywords: SARS-CoV-2; coronavirus; emerging infectious diseases; interspecies transmission; zoonosis.

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The Extended Impact of Human Immunodeficiency Virus/AIDS Research

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Tara A Schwetz, Anthony S Fauci, The Extended Impact of Human Immunodeficiency Virus/AIDS Research, The Journal of Infectious Diseases , Volume 219, Issue 1, 1 January 2019, Pages 6–9, https://doi.org/10.1093/infdis/jiy441

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Human immunodeficiency virus (HIV) is one of the most extensively studied viruses in history, and numerous extraordinary scientific advances, including an in-depth understanding of viral biology, pathogenesis, and life-saving antiretroviral therapies, have resulted from investments in HIV/AIDS research. While the substantial investments in HIV/AIDS research are validated solely on these advances, the collateral broader scientific progress resulting from the support of HIV/AIDS research over the past 30 years is extraordinary as well. The positive impact has ranged from innovations in basic immunology and structural biology to treatments for immune-mediated diseases and cancer and has had an enormous effect on the research and public and global health communities well beyond the field of HIV/AIDS. This article highlights a few select examples of the unanticipated and substantial positive spin-offs of HIV/AIDS research on other scientific areas.

The first cases of AIDS were reported in the United States 37 years ago. Since then, >77 million people have been infected worldwide, resulting in over 35 million deaths. Currently, there are 36.9 million people living with human immunodeficiency virus (HIV), 1.8 million new infections, and nearly 1 million AIDS-related deaths annually [ 1 ]. Billions of research dollars have been invested toward understanding, treating, and preventing HIV infection. The largest funder of HIV/AIDS research is the National Institutes of Health (NIH), investing nearly $69 billion in AIDS research from fiscal years 1982–2018. Despite the staggering disease burden, the scientific advances directly resulting from investments in AIDS research have been extraordinary. HIV is one of the most intensively studied viruses in history, leading to an in-depth understanding of viral biology and pathogenesis. However, the most impressive advances in HIV/AIDS research have come in the arena of antiretroviral therapy. Before the development of these life-saving drugs, AIDS was an almost universally fatal disease. Since the demonstration in 1987 that a single drug, zidovudine, better known as azidothymidine or AZT, could partially and temporarily suppress virus replication [ 2 ], the lives of people living with HIV have been transformed by the current availability of >30 antiretroviral drugs that, when administered in combinations of 3 drugs, now in a single daily pill, suppress the virus to undetectable levels. Today, if a person in their 20s is infected and given a combination of antiretroviral drugs that almost invariably will durably suppress virus to below detectable levels, they can anticipate living an additional 50 years, allowing them almost a normal life expectancy [ 3 ]. In addition, a person receiving antiretroviral therapy with an undetectable viral load will not transmit virus to their uninfected sexual partner. This strategy is referred to as “treatment as prevention” [ 4 ]. Also, administration of a single pill containing 2 antiretroviral drugs taken daily by an at-risk uninfected person decreases the chance of acquiring HIV by >95%. Finally, major strides are being made in the quest for a safe and effective HIV vaccine [ 5 ].

The enormous investment in HIV research is clearly justified and validated purely on the basis of advances specifically related to HIV/AIDS. However, the collateral advantages of this investment above and beyond HIV/AIDS have been profound, leading to insights and concrete advances in separate, diverse, and unrelated fields of biomedical research and medicine. In the current Perspective, we discuss a few select examples of the positive spin-offs of HIV/AIDS research on other scientific areas ( Table 1 ).

Positive Spin-offs of Human Immuno deficiency Virus/AIDS Research on Other Areas of Medicine

Abbreviation: HIV, human immunodeficiency virus.

Regulation of the Human Immune System

Congenital immunodeficiencies have been described as “experiments of nature,” whereby a specific defect in a single component of the complex immune system sheds light on the entire system. Such is the case with AIDS, an acquired defect in the immune system whereby HIV specifically and selectively infects and destroys the CD4 + subset of T lymphocytes [ 6 ]. In this respect, HIV infection functions as a natural experiment that elucidates the complexity of the human immune system. The selectivity of this defect and its resulting catastrophic effect on host defense mechanisms, as manifested by the wide range of opportunistic infections and neoplasms, underscore the critical role this cell type plays in the overall regulation of the human immune system. This has provided substantial insights into the pathogenesis of an array of other diseases characterized by aberrancies of immune regulation. Additionally, the in-depth study of immune dysfunction in HIV disease has shed light on the role of the immune system in surveillance against a variety of neoplastic diseases, such as non-Hodgkin lymphoma and Kaposi sarcoma. As a result of its association with HIV/AIDS, Kaposi sarcoma was discovered to be caused by human herpesvirus 8 [ 7 ].

Targeted Antiviral Drug Development

Targeted antiviral drug development did not begin with HIV infection. However, the enormous investments in biomedical research supported by the NIH and in drug development supported by pharmaceutical companies led to highly effective antiretroviral drugs targeting the enzymes reverse transcriptase, protease, and integrase, among other vulnerable points in the HIV replication cycle, and have transformed the field of targeted drug development, bringing it to an unprecedented level of sophistication. Building on 3 decades of experience, this HIV model has been applied in the successful development of antiviral drugs for other viral diseases, including the highly effective and curative direct-acting antivirals for hepatitis C [ 8 ].

Probing the B-Cell Repertoire

The past decade has witnessed extraordinary advances in probing the human B-cell lineage resulting from the availability of highly sophisticated technologies in cellular cloning and genomic sequencing [ 9 ]. AIDS research aimed at developing broadly reactive neutralizing antibodies against HIV and an HIV vaccine that could induce broadly neutralizing antibodies has greatly advanced the field of interrogation of human B-cell lineages, leading to greater insights into the humoral response to other infectious diseases, including Ebola [ 10 ], Zika [ 11 ], and influenza [ 12 ], as well as a range of autoimmune, neoplastic, and other noncommunicable diseases [ 13 ].

Structure-Based Vaccine Design

Although a safe and effective HIV vaccine has not yet been developed, the discipline of structure-based vaccine design using protein X-ray crystallography and cryoelectron microscopy has matured greatly in the context of HIV vaccine research. The design of immunogens based on the precise conformation of epitopes in the viral envelope as they bind to neutralizing antibodies has been perfected within the arena of HIV vaccine immunogen design. This has had immediate positive spinoffs in the design of vaccines for other viruses, such as respiratory syncytial virus, in which the prefusion glycoprotein was identified as the important immunogen for a vaccine using structure-based approaches [ 14 ].

Advances in HIV/AIDS-Related Technologies

Insights into the basic immunology of HIV drove the development and optimization of several broadly applicable technologies. Using inactivated HIV as a means of altering T lymphocytes to modulate the immune response, safe lentiviral gene therapy vectors are now US Food and Drug Administration–approved to treat certain cancers (eg, acute lymphoblastic leukemia) [ 15 ]. Additionally, it was discovered early in the epidemic that HIV is associated with the loss of CD4 + T lymphocytes [ 16 ]. While much of the initial research on CD4 + T lymphocytes was possible due to existing flow cytometry technologies, probing the complexities of immune dysregulation in HIV infection spurred the development of multicolor cytofluorometric technologies that have proven extremely useful for studying a variety of other diseases characterized by immune dysfunction [ 17 ]. The reality of utilizing these technologies in resource-poor areas accelerated the advancement of new simplified, automated, affordable, and portable point-of-care devices with broader implications for clinical medicine [ 18 ].

Role of Immune Activation in Disease Pathogenesis

Studying the pathogenesis of HIV disease has clearly demonstrated that aberrant immune activation stimulated by virus replication is the driving force of HIV replication [ 19 ]. In essence, the somewhat paradoxical situation exists whereby the very immune activation triggered by the virus in an attempt to control virus replication creates the microenvironment where the virus efficiently replicates. Even when the virus is effectively suppressed by antiretroviral drugs, a low degree of immune activation persists [ 20 ]. In this regard, the flagrant immune activation associated with uncontrolled virus replication, as well as the subtle immune activation associated with control of virus replication, are important pathogenic triggers of the increased cardiovascular and other organ system diseases associated with HIV infection. This direct association of even subtle levels of immune activation seen in HIV infection with a variety of systemic diseases has led to considerable insight into the role of immune activation and inflammation in human disease [ 21 ]. For example, recognition of the increased incidence of heart disease in the HIV population that is associated with chronic inflammation has stimulated interdisciplinary advances in understanding and treating coronary heart disease apart from HIV infection [ 22 ].

Comorbidities in HIV Disease

Antiretroviral therapy, which has transformed HIV treatment, is shifting the incidence of certain diseases in people living with HIV. Even when well-controlled by antiretrovirals, HIV disease is associated with an increased incidence of diseases, such as cardiovascular disease, kidney and liver disease, the premature appearance of pathophysiologic processes associated with aging, and several cancers [ 21–24 ]. This is especially true for non-AIDS-defining cancers, whose incidence rates are increasing while AIDS-defining cancer rates are decreasing [ 24 ]. In lower-income countries, tuberculosis is a common coinfection with HIV, and HIV coinfection was shown to be a key risk factor for progression of latent Mycobacterium tuberculosis infection to active disease [ 25 ]. There are a variety of ongoing studies [ 21 ] investigating the pathogenic bases of these conditions to shed greater insight into their causes and potential interventions that might impact these diseases apart from HIV infection and immunodeficiency.

The collateral advantages resulting from the substantial resources devoted to HIV/AIDS research over the past 30 years are extraordinary. From innovations in basic immunology and structural biology to treatments for immune-mediated diseases and cancer, the conceptual and technological advances resulting from HIV/AIDS research have had an enormous impact on the research and public and global health communities over and above the field of HIV/AIDS. The HIV/AIDS research model has proven that cross-fertilization of ideas, innovation, and research progress can lead to unforeseen and substantial advantages for a variety of other diseases.

Acknowledgments.  The authors thank Carl Dieffenbach, Daniel Rotrosen, Charles Hackett, and Robert Eisinger for their helpful input in preparation of the manuscript.

Potential conflicts of interest.  Both authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Climate change and infectious disease: a review of evidence and research trends

• Paige Van de Vuurst 1 , 2 , 3 &
• Luis E. Escobar   ORCID: orcid.org/0000-0001-5735-2750 2 , 3 , 4 , 5  

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Climate change presents an imminent threat to almost all biological systems across the globe. In recent years there have been a series of studies showing how changes in climate can impact infectious disease transmission. Many of these publications focus on simulations based on in silico data, shadowing empirical research based on field and laboratory data. A synthesis work of empirical climate change and infectious disease research is still lacking.

We conducted a systemic review of research from 2015 to 2020 period on climate change and infectious diseases to identify major trends and current gaps of research. Literature was sourced from Web of Science and PubMed literary repositories using a key word search, and was reviewed using a delineated inclusion criteria by a team of reviewers.

Our review revealed that both taxonomic and geographic biases are present in climate and infectious disease research, specifically with regard to types of disease transmission and localities studied. Empirical investigations on vector-borne diseases associated with mosquitoes comprised the majority of research on the climate change and infectious disease literature. Furthermore, demographic trends in the institutions and individuals published revealed research bias towards research conducted across temperate, high-income countries. We also identified key trends in funding sources for most resent literature and a discrepancy in the gender identities of publishing authors which may reflect current systemic inequities in the scientific field.

Conclusions

Future research lines on climate change and infectious diseases should considered diseases of direct transmission (non-vector-borne) and more research effort in the tropics. Inclusion of local research in low- and middle-income countries was generally neglected. Research on climate change and infectious disease has failed to be socially inclusive, geographically balanced, and broad in terms of the disease systems studied, limiting our capacities to better understand the actual effects of climate change on health.

Graphical abstract

The Intergovernmental Panel on Climate Change has anticipated, with high confidence, that climate change will amplify health threats worldwide [ 1 , 2 ], which is supported by the fact that the life cycles of many infectious agents are inextricably linked to climate [ 1 , 3 , 4 , 5 , 6 ]. Multiple studies have shown that variation in temperature, precipitation, and humidity affects the transmission and distribution of infectious diseases [ 7 , 8 , 9 , 10 ]. Nevertheless, the magnitude, direction, and strength of the impact of climate change upon infectious disease transmission remains unclear [ 3 , 5 , 7 ]. To determine what further research is needed to advance a given field in scientific research it is often necessary to synthesize previous work [ 11 ]. This type of retrospective, systematic analysis of literature in a specific topic or field is referred to as a systematic review. Systematic reviews are a popular and effective method commonly utilized to identify trends and gaps in ongoing research [ 12 ]. Results from systematic reviews and scoping studies, which are often used to map the availability of literature on an specific topic [ 13 , 14 ], can be used to guide future research lines, future policy decisions, and can be particularly useful in scientific fields with emerging evidences, such as epidemiology [ 12 , 13 , 15 , 16 ].

Despite their effectiveness, systematic reviews are noticeably lacking in the literary landscape of anthropogenic climate change research, especially with regard to its impacts on infectious diseases. There is, therefore, a need for a systematic synthesis of recent empirical research assessing disease impacts of climate change. Here, we provide a synthesis of scientific literature on climate change and infectious diseases from recent history. The overall objective of this study was to determine the trends of recent empirical research regarding climate change impacts on infectious diseases and to identify geographic, topical, or taxonomic trends of research. We sought to assess the geographic regions where climate change and disease transmission have been under studied, accounting for both study area and first author affiliation to identify geographic and bibliometric signals. In addition, we assessed the taxa of hosts and transmission types of pathogens studied. Finally, we sought to inform future research avenues, policy, and practices via the trends and impacts identified herein.

Search strategy, inclusion criteria, exclusion criteria

Our search strategy included recovering articles from Web of Science (Clarivate™) [ 17 ] and PubMed™ [ 18 ] literary repositories using a key word search. Keywords included "climate change", "global warming", “greenhouse gas*” (*asterisk used to incorporate all forms of the word. i.e., gas, gases, gaseous), “world warming”, “disease”, “infectious”, “pathogen”, “waterborne”, “water borne”, “food borne”, “vector borne”, “parasite”, and “non-vector borne”. Time range restrictions were set from January of 2015 to December of 2020 to incorporate all publications from the most recent, pre-pandemic five-year period of empirical climate change research. This key word search was limited to journal manuscripts, as the purpose of this study was to analyze original peer-reviewed research. Other literature types such as book chapters, review articles, proceedings papers, or conference abstracts were excluded. Articles were then imported into Endnote citation software, where redundant articles were removed.

After collection we conducted an initial screening of both article titles and abstracts. This initial review allowed for the identification of articles which did not fit within the review criteria. Inclusion criteria were: (1) The manuscript was peer-reviewed and published without retraction, (2) the primary goal of the research was centered on assessing climate change and its repercussions, impacts, effects, association, or influences on disease, infection, transmission, infestation, or illness, (3) the research was original and not a review, (4) the research was descriptive, retrospective, and based on real world systems using non-simulated future-climate data (i.e., present-day and past climate only), (5) the manuscript utilized primary data and (6) the pathogen, parasite, vector, or disease of focus impacted either humans, non-human animals, or both. Each article was reviewed by at least two independent reviewers and was confirmed for inclusion or exclusion based on the inclusion criteria. If the independent reviewers were in disagreement on whether or not the article fit the inclusion criteria, the article was reviewed by a third reviewer. Studies which did not fit this inclusion criteria were flagged and maintained in a separate databased. Studies on plant diseases were not within the scope of this study and therefore were excluded.

Evidence extraction and analysis

We then reviewed the remaining publications in full and conducted evidence extraction of each article to conduct our gap analysis of bibliometric, subject, taxonomic, and geographic trends in research and publication. We gathered descriptive metadata from each article to assess when, where, and by whom the articles were published (e.g., year or publication, journal name, title, authors, etc.). To assess authorship demographics, we recorded the lead author and senior author’s names, pronouns, and institutional affiliation for each publication. Authors’ pronouns were recorded based upon the personal distinctions of each individual author, and the pronouns they chose to use (e.g., she/her, he/him, they/them, em/eir, xem/xyr, etc.) on their institutional or research affiliated websites. We implemented this method to be inclusive of all authors’ identities while maintaining personal privacy [ 19 , 20 ]. If the author did not denote their pronouns in any public way, we recorded their pronouns as “unknown”. We also collected descriptive metadata on the study methods and locations or each article including: (1) study location at the country and continent level, (2) disease host, vector, or pathogen studied, (3) transmission method of each disease studied, (4) primary taxa or taxon of interest (i.e., the taxonomic group of the host or infectious organism or organisms being studied), and (5) spatial scale (e.g., local or inferior to country level, regional, country level, or global). To assess the quality of the included literature, we also recorded and synthesized the conclusions of the sampled articles, and reported these findings based upon the author’s interpretation of their results. We also collected descriptive information on the publication funding or support for each article published in the most recent year included in the review (i.e., 2020) to ascertain current funding sources for the most recent climate change and disease publications. We then compared funding sources with current estimates of country gross domestic product (GDP) from the World Bank World Development Indicators Dataset [ 21 ].

To assess the distribution of the categorical topics of the literature we used a Pearson’s chi-squared ( χ 2 ) test. It has been estimated that approximately 60% of known infectious diseases are zoonotic (i.e., originating in non-human animals) [ 16 , 22 ]. We compared this value (60%) with the proportion of literature which assessed zoonotic diseases to identify if the literature followed this expected proportion. We also used the χ 2 test to identify if the proportion of host species categories studied (humans, wildlife, and livestock) were equal. To assess the geographic distribution of publication demographics, the lead authors’ institutional affiliations were recorded for each publication and assigned to their corresponding countries of origin. Demographic data of study locations and author affiliations were summarized and visualized to detect spatial and temporal patterns of these data using ArcGISpro version 2.9.3 and R version 4.1 [ 23 , 24 , 25 ]. We utilized population data from the United Nations Population Division [ 26 ] for the year 2020 to assess the per-capita research effort by country.

Literature demographics

Our initial key word search resulted in 10,461 articles from both PubMed and Web of Science. A total of 621 research articles (5.9%) fit the inclusion criteria for the 2015–2020 period and were retained for evidence extraction and gap analysis. Within these publications, 109 distinct infectious diseases were identified in relation to climate change research. A small portion of publications ( n  = 127) assessed multiple diseases within the same study. Authors of the reviewed articles reported that climate change impacted the disease system being assessed in 59% of the articles. Most of the articles (83.9%) which described climate change impacts reported that climate change increased the prevalence, transmission, or suitability for the disease being studied, while 11.5% of studies reported that climate change decreased the prevalence, transmission, or suitability. Only 7.7% of the assessed articles reported no effect of climate change on the disease system being studied. The review revealed that 32.7% of the articles concluded that climate change could “possibly” or “potentially” impact the disease system being assessed (i.e., the authors did not report a definitive pattern).

Research trends

Infectious diseases which originate from cross-species pathogen transmission of animals to humans (i.e., zoonotic diseases) accounted for most of the studies ( n  = 288, 46.4%), significantly more than diseases which do not originate from animal to human cross species transmission ( n  = 253, 40.7%), ( χ 2  = 9.97, P  = 0.002). Infectious diseases which impact humans were well represented within the literature ( n  = 406) ( χ 2 = 114.3, P  = 0.0001), while infectious diseases affecting livestock were less represented ( n  = 152). Only 116 publications assessed diseases affecting wildlife.

The specific conditions most frequently studied from this sample included vector-borne diseases (Fig.  1 ), such as malaria ( n  = 58), dengue fever ( n  = 37), and Lyme disease ( n  = 22) (Fig.  1 ). Vectors most frequently studied were mosquitoes ( n  = 174), ticks ( n  = 51), and flies ( n  = 14) (Fig.  1 ). Frequently studied environmentally transmitted conditions included food and water-borne diseases, such as diarrheal diseases ( n  = 18) and chytridiomycosis ( n  = 10) (Fig.  1 ). Studies also focused on diseases hosted by arthropods ( n  = 189) and humans ( n  = 185) (Fig.  1 ). The third most studied host taxonomic group was non-human mammals ( n  = 47), followed by amphibians ( n  = 19) and birds ( n  = 17) (Fig.  1 ). In terms of study scale, research was conducted at the local, regional, or country levels, with less effort for global-level studies (Fig.  2 ).

Trends in climate change and disease research. Number of publications ( x -axis) from 2015–2020 according to A taxa of host species studied, B transmission type of diseases studied, C vector species studied, and D top 20 most studied diseases from over 100 different diseases studied. Multiple: multiple diseases with multiple transmission types studied in a single article

Bibliometric demographics. A Number of publications ( x -axis) from 2015–2020 when delimited by scale of study. N/A: Studies for which a spatial scale was not applicable (e.g., laboratory-based studies) or for which scale was not specified. B Percentile breakdown of lead author affiliations collated into categories based on the institution’s description (i.e., college or university, governmental organizations or research organization). Other: lead author affiliation institutions which do not fit one of these categories including non-governmental organizations, independent researchers, or private companies not otherwise specified

Publication trends

Bibliometric analysis revealed a greater usage of he/him pronouns for both first and senior authors (Fig.  3 ). We recorded no instances of they/them or other non-binary pronouns by first or senior authors from the articles revised. We also found that study areas and affiliation of lead authors most frequently occurred in the United States, China, the United Kingdom, Canada, and Australia (Figs.  4 , 5 ). Research effort accounting for the country’s population size showed that countries such as Norway, Australia, and Canada have a higher comparative research effort than other countries (Fig.  4 ). Most lead author affiliations were linked to higher education institutions (i.e., universities or colleges), with fewer publications originating from governmental organizations or independent research institutions (Fig.  2 ). University affiliations were frequently located in the United States (e.g., the University of California, Colorado State University, University of Florida), and in China (e.g., Shandong University) (Fig.  5 ). Funding for papers published in 2020 was largely sourced from federal or national institutions (53.3% of articles) or a combination of federal and academic institutions (26.7% of articles), with most of this funding originating in high income countries such as the United States, Canada, Germany, and the United Kingdom (Supplementary Fig. 1). Information of funding sources from lower income countries was limited, with only one country (Greece) having a GDP below the top 50 of reported counties based on World Bank estimates [ 21 ]. Non-governmental organizations and local agencies made up a modest proportion of funding sources for the total of articles published (20%).

Author pronouns on climate change and infectious disease research. The self-identified pronouns of A first authors and B last (senior) authors of articles on climate change and disease from 2015 to 2020. The disparity between he/him pronoun usage over other pronouns was pronounced for senior authors. Authors’ pronoun usage in public settings may vary from their gender identities

Map of study locations by country. A The geographic representation of where studies were conducted (i.e., country where the data analyzed in the study originated) from 2015–2020 on climate change and infectious disease and B publications that fit the inclusion criteria as a proportion of human population in 2020 (per one million individuals). Population data were collected from the United Nations Population Division [ 26 ]. Darker color represents more publications conducted in or on the corresponding country. Grey indicates that no studies which fit the inclusion criteria were conducted in or on the corresponding countries. Shape file for map creation sourced from DIVA-GIS [ 84 , 85 ]

Map of lead author affiliation origins. The geographic representation of lead author affiliation origins for research on climate change and disease from 2015 to 2020. Darker color represents more publications originating from the corresponding country. Grey indicates that no studies which fit the inclusion criteria were conducted by authors affiliated with the corresponding countries. Blue points indicate the top ten publishing institutions globally for climate change and disease. Shape file for map creation sourced from DIVA-GIS [ 84 , 85 ]

Through this study we have revised the major trends in the current literature on climate change and infectious diseases. Our assessment identified both topical and geographic biases in the climate change and disease research arena. More specifically, we found that there was a notable focus on diseases which impact humans and upon arthropod-borne pathogens. Taxonomic bias, or the emphasis of study on specific organisms [ 27 ], has previously been identified in biodiversity and conservation science research [ 28 , 29 , 30 ]. Our results have identified taxonomic biases toward mammalian hosts and arthropod-borne pathogens and in climate change and infectious disease research. When certain taxa are over-represented in various scientific fields it is possible for them to draw both attention and funds away from less understood taxa [ 28 ]. It is possible that taxonomic bias has impacted the study of climate change and infectious disease by skewing research toward specific disease systems, suggesting an anthropocentric research approach potentially influenced by external forces, such as public health funding and disease burden [ 31 , 32 ]. Vector-borne diseases have considerable burden on human health, killing approximately 700,000 people annually [ 33 ]. A research emphasis on diseases affecting humans is, therefore, potentially unsurprising as human health is a driving force behind many research efforts and encompasses a large proportion of research and development funding [ 34 , 35 ]. Other research has shown that societal pressures correlate with taxonomic bias [ 28 ], which could explain why human-only and zoonotic diseases were so heavily studied as well.

Despite the anthropocentric nature of our results, many understudied taxa, such as amphibians, birds, and aquatic invertebrates, have higher risks of extinction due to infectious diseases than humans or other mammals [ 36 , 37 , 38 ]. Taxonomic bias in the study of infectious disease is concerning, as a lack of research effort could limit the understanding of diseases systems for threatened or endangered taxa. This in turn limits our capacities to understand how, where, and why diseases emerge in the wild. Risks of climate change impacts on lesser studied groups, such as wildlife and livestock, could still have public health effects due to spillover transmission of unknown pathogens [ 22 , 39 ]. The dearth of research on wildlife diseases could also lead to gaps of knowledge. Infectious diseases may harm ecological balance by reducing wildlife populations and decreasing overall biodiversity [ 40 , 41 , 42 ]. A large body of literature shows that ecological imbalances and biodiversity loss have detrimental effects on human health as well [ 39 , 43 , 44 , 45 ]. For instance, decreases in diversity of wildlife has been associated with increases risk of hantavirus spillover transmission from rodents to humans [ 46 , 47 , 48 , 49 ]. Public health efforts to study climate change and human health should consider biodiversity dimensions of spillover transmission for a more holistic ecosystem health approach.

We found that most lead authors were linked to higher-education institutions (i.e., universities or colleges), with fewer publications originating from governmental organizations or independent research institutions (Fig.  2 ). This bias towards academic-based research is not surprising considering that higher-education institutions often focus efforts on research and disseminating knowledge [ 50 ]. This result also indicates a poor active participation of stakeholders in governing bodies on climate change and health research, which could explain the slow progress of international policy on climate change and disease research. It is important to note, however, that most funding for the support of recent research publications originated from federal or national institutions (Additional file 1 : Fig. S1). While funding agencies constitute important stakeholders in the scientific publication process, agendas from funding sources may bias the research topics and discoveries reported [ 51 , 52 ]. For instance, publications with corporate funding are more likely to contribute to the polarization or politicization (i.e., contributing to the tension between political ideologies or identities) of climate change related topics [ 53 ]. We found that most articles reviewed for funding sources did not receive funding from corporate or industry agencies. Government funding is the main driver of science and provides research directions for non-government funding sources [ 52 ]. As such, an increase in government funding for climate change and infectious disease research accounting for environmental justice could transform the landscape of public and private research funding opportunities to reduce the inequities presented here. An increase in funding in the social science aspects of climate change may also facilitate the framing of climate change as a global social challenge, rather than a purely scientific endeavor with limited social legitimacy [ 54 ].

We also found that there was greater usage of he/him pronouns by lead and senior authors across the articles revised, suggesting that more male or male identified authors were present than female or female identified authors (Fig.  3 ). Gender discrepancies in authorship were more notable for senior authorship than for first authorship, which appears to be a general pattern in academic authorship inequity [ 55 ], even with increased authorship by women in recent decades [ 56 ]. Until recently, women or female-identified authors comprise a minority of researchers and trainees in science in general, which has resulted in authorship inequities that are expected to persist for some time [ 56 ]. Gender persistant inequity in authorship is specifically conerning within the field of climate change and infectious disease research due to its cross cutting social implications. Women are expected to experience greater climate change and health impacts as a result of their social and economic positions, and cultural discrimination [ 57 ]. As such it is important that women’s viewpoints and experiences are represented within the scientific literature to develop more effective and inclusive policies for climate change adaptation and mitigation.

In terms of geographic scale and location, we found that most climate change and infectious disease research was conducted at the regional and local scales (Fig.  2 ), suggesting that fine-scale studies dominate the field and our understanding of climate change impacts on human and animal health. Climate change and disease research also occurred principally in temperate areas (e.g., North America, Europe) rather than in tropical areas (e.g., sub-Saharan Africa, Latin America, and Pacific Southeast Asia) (Figs.  4 , 5 ). This spatial bias is present even when publications were corrected for country population. The research effort discrepancy between temperate vs tropical regions is concerning considering that tropical areas are the most at risk for emerging infectious diseases impacts [ 58 , 59 ]. Tropical areas are also experiencing drastic climate change effects, including reductions in food availability in short periods [ 60 ]. Tropical areas having limited to no climate change and disease research included Latin America, Northern and West Africa, and the Indo-pacific (Figs.  3 , 4 ). Furthermore, climate change is expected to increase the areas suitable for infectious agents in land and aquatic ecosystems [ 10 , 61 ]. For instance, the aquatic pathogen Vibrio cholerae , the causative agent of cholera, is expected to increase in regions where we found limited research effort [ 61 , 62 ]. Other areas which did not receive substantive research effort include extremely cold Arctic or Subarctic areas of Eurasia (Fig.  4 ). Permafrost regions such as these have recently experienced outbreaks of avian influenza (H5N1) [ 63 ], and previous reviews have identified melting permafrost as a reservoir of potentially viable and uncharacterized pathogens [ 64 ]. As such, a constituted effort to elucidated emerging infectious diseases in these regions should be undertaken to mitigate the risks of disease emergence. The confluence of susceptibility to both climate change impacts and infectious disease suggests a need for research in underrepresented areas reported here. Furthermore, underrepresentation of countries and human communities already disenfranchised and at greater risk for encountering infectious disease amplifies social inequity [ 7 ].

One caveat of our assessment is that publications from lower income or developing countries may not have been indexed in the publication data repositories accessed (i.e., Web of Science and PubMed) due to publication barriers such as language, publication fees, or lack of equitable partnerships or collaborative networks [ 65 , 66 , 67 , 68 , 69 ]. The potential misrepresentation of science from low-income countries highlights a possible equity issues within the dissemination of research which, in turn, could lead to the exclusion of relevant discoveries in the global health agenda [ 68 , 69 , 70 ]. A confirmation or publication bias could also be present in our results, as seen by the high number of papers which positively identified a climate change impact on infectious diseases. Previous research has commented on the scientific culture and potential dangers associated with the current emphasis on publishing only “significant” or “positive” results [ 71 , 72 , 73 , 74 ]. It is possible that researchers were reluctant or unable to publish negative or inconclusive results, thus skewing the conclusions of this sample. Furthermore, while we found that many articles either found a definitive climate change impact, or concluded that climate change could “possibly” or “potentially” impact the disease system being assessed, these findings were based upon the author’s interpretation of their results and may be an exaggerated interpretation of the data. Finally, while we sought to identify the distribution of authorship via author pronoun usage, there could be discrepancies present between the pronouns publicly available for the authors and the gender identities they have privately. This discrepancy is to be expected considering the discriminatory practices in academia against lesbian, gay, bisexual, transgender, and queer (LGBTQ+) scientists [ 75 , 76 , 77 ].

We found that both geographic and taxonomic trends were present in recent studies assessing climate change and the burden of infectious disease. The majority of research was focused on vector-borne pathogens and was conducted in well-developed, high-income countries with temperate climates, neglecting directly-transmitted diseases in tropical regions. The anthropocentric signal in research effort may contribute to a lack of understanding of climate change effects on wildlife systems. The underrepresentation of some taxonomic groups of pathogens and hosts, pathogen transmission types, and geographic areas should be of global health concern, as areas and diseases neglected may become sources of emerging zoonotic diseases. An ecosystem-based framework to study disease responses to climate change could mitigate topical and taxonomic biases identified here. Viral zoonoses outbreaks at the local level in underrepresented countries such as Madagascar, Saudi Arabia, and Indonesia have led to prolific human epidemics of plague, Middle East respiratory syndrome, and cholera in recent years [ 78 ], highlighting the need for more research in regions underrepresented in the literature. The recent coronavirus disease pandemic also highlights the need for more research on directly transmitted pathogens circulating in wildlife [ 79 ]. Furthermore, research is still needed to understand the linkages between patterns of research funding with climate change and infectious disease studies. Understanding the funding landscape (e.g., agencies prioritizing certain regions, diseases, and topics) could further elucidate the relationship between research bias, research equity, and funding allocation.

The impact of climate change research on intergovernmental policy and vice versa is both tractable and increasingly important [ 80 , 81 ]. Policy changes to address the biases presented here, including the diseases studied, areas, and identities of leading authors, should be prioritized by both funding agencies and the scientific community. Policy change could include, for example, the prioritization of infectious disease research and surveillance at the human-wildlife interface within the context of climate change, funding prioritizing scientists from minority groups, and neglected geographic regions. Addressing research inequity will help build human capacity, surveillance, and scientific infrastructure to better prepare and strengthen the global health response to climate change threats [ 82 ]. Furthermore, research foundations in high-income countries should implement and maintain inclusive-collaboration practices to value contributions by local scientists in countries underrepresented in this review to advance research equity as a means towards effective prevention of future emerging diseases from their sources. Building political and social support behind climate change and infectious disease research will be essential under the expected rates of climatic variation in the near future [ 83 ]. In conclusion, there is an urgent need to increase research effort for neglected disease systems and geographies, and there is a need to re-examine aspects of environmental justice from the scientists leading these studies to the local beneficiaries for the advancement of infectious diseases research in the context of climate change.

Availability of data and materials

Not applicable.

Abbreviations

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Acknowledgements

Authors thank Sarah M. Karpanty, Mark Ford, Steven N. Winter, Mariana Castaneda-Guzman, Diego Soler-Tovar, Caroline Ilse, Abigail Parch, Tabatha Gentry, David Treanor, Alma Talcott, and Victor Jose Catalan who contributed greatly to the completion of this work.

This study was supported by the National Science Foundation award: Human–Environment and Geographical Sciences Program (2116748), the Institute for Critical Technology and Applied Science, Virginia Tech: ICTAS-JFP-2022-2023 program, and the Virginia Tech College of Natural Resources and Environment Environmental Security Grant program.

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Van de Vuurst, P., Escobar, L.E. Climate change and infectious disease: a review of evidence and research trends. Infect Dis Poverty 12 , 51 (2023). https://doi.org/10.1186/s40249-023-01102-2

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Alan Dangour on reframing climate change as a health crisis

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• Alan Dangour, Director of Climate and Health at Wellcome, is working to highlight the profound links between climate change and human health, moving beyond traditional climate metrics to focus on lives at risk.
• Wellcome’s Climate and Health program aims to strengthen the evidence base on climate-sensitive health issues, such as heatwaves and the spread of infectious diseases, while translating research into practical, policy-driven solutions.
• Dangour emphasizes the need for interdisciplinary collaboration between researchers, policymakers, and communities to develop real-world interventions, such as cooling strategies during extreme heat and addressing maternal health risks.
• Wellcome seeks to leverage technology, such as AI, to enhance research dissemination and build a thriving, global field of climate and health research, ensuring health is central to climate action policies.

The notion that climate change poses a significant health risk is not as widely acknowledged as it should be. Yet the relationship between a warming planet and human well-being is profound, with impacts ranging from heat waves to the spread of infectious diseases. Alan Dangour, Director of Climate and Health at Wellcome, is determined to change that. 

“Developing evidence-based solutions to the damage to our health done by climate change is genuinely vital,” Dangour told Mongabay during a recent exchange with Matthew Boyer, reflecting his mission to place health at the center of climate action.

Dangour’s journey at the nexus of human well-being and the environment began well before joining Wellcome in January 2022. As a Professor of Food and Nutrition for Global Health at the London School of Hygiene and Tropical Medicine, he dedicated years to studying the intersections of environmental change, food systems, and public health. His time in academia highlighted the increasing toll that climate change was taking on health, a theme that has only grown more pressing. Today, at the helm of Wellcome’s Climate and Health program, Dangour leads a team focused on translating research into practical, policy-driven solutions that protect communities from the health consequences of a rapidly changing climate.

While the concept of climate change as a public health issue is not new, its mainstream inclusion remains limited. For many, the conversation around climate remains centered on atmospheric science, energy policies, and sea level projections. Dangour’s work aims to recalibrate this discourse. “When talking about the impact of climate change, we need to move beyond measuring this in degrees Celsius, carbon emissions and sea level rises and start evaluating the climate crisis in terms of lives at risk and the work towards protecting them,” he argues. By framing climate change as a health crisis, Dangour and his team hope to catalyze more immediate and impactful actions.

The Wellcome Climate and Health program seeks to strengthen the evidence base for how climate change affects health, from heat waves to the spread of climate-sensitive diseases like dengue fever. For Dangour, these connections are clear: “We’re increasingly experiencing extreme heat and the spread of climate-sensitive infectious diseases, such as dengue, in areas where they have not historically been a major issue, further north in Europe and America.” The geographical spread of such diseases, accelerated by rising global temperatures, serves as a stark reminder of the urgency to act.

But the challenge goes beyond merely understanding these health risks. One of the program’s central goals is ensuring that research translates into real-world solutions. That means not just publishing findings, but embedding them into the policy decisions that shape public health. 

“We want to fund research that leads to action in the real world and offers practical solutions to address climate and health issues,” Dangour explained via email. To do so, Wellcome seeks to foster collaboration between researchers, policymakers, and communities. By supporting transdisciplinary approaches, they aim to break down the silos that too often limit progress.

A case in point is Wellcome’s research on extreme heat. The risks posed by heatwaves are clear: they strain the body’s ability to regulate temperature, leading to heat exhaustion and potentially fatal heat stroke. Elderly populations, infants, and those with chronic conditions are particularly vulnerable. To address these challenges, Wellcome is funding research that investigates community-specific interventions, from planting trees to cool agricultural workers, to testing the efficacy of cool-roof coatings in keeping indoor spaces habitable during periods of extreme heat.

Climate change also exacerbates gender-specific health risks. Dangour points to the example of maternal health, where extreme heat has been shown to increase risks during pregnancy. 

“The impact that extreme heat has on maternal health is well documented, but we currently lack detailed understanding of the biological mechanisms involved,” he said. This gap in knowledge is exactly the kind of challenge that Wellcome seeks to address by supporting new research that can inform more effective public health interventions.

While the immediate focus of Wellcome’s efforts is on better understanding and mitigating the health impacts of climate change, the program’s broader ambition is to create a thriving field of climate and health research. This involves building a robust infrastructure that allows researchers to work across disciplines and countries. It also includes leveraging technology, such as artificial intelligence, to accelerate the synthesis and dissemination of evidence. 

“In the future, it would be amazing to have an open-access AI tool that automatically updates evidence syntheses as studies are published,” Dangour noted, pointing to the potential for cutting-edge technologies to enhance how we generate and apply knowledge.

Beyond research, Wellcome plays a crucial role in convening different stakeholders, from government bodies to local communities, to push for health-centered climate policies. 

“Philanthropic organizations are in a unique position to help convene stakeholders from community groups to researchers to policymakers to help affect change,” Dangour asserted. 

This convening power, he believes, is key to ensuring that climate change is no longer discussed in abstract terms but in ways that relate directly to people’s everyday lives and health.

Ultimately, Dangour’s vision is for a world where health is central to all climate discussions. By embedding health into climate policies and actions, Wellcome aims to not only mitigate the harms of climate change but also create healthier, more resilient societies. For Dangour, this is both an urgent priority and a long-term commitment. 

“We are working towards a healthier and more sustainable world where local communities and national governments are fully equipped to use evidence-based interventions to tackle climate and health emergencies,” he said.

The work may be daunting, but for Dangour, the path forward is clear: interdisciplinary research, robust evidence, and, most importantly, translating that evidence into action. The stakes are high, but so too is the potential to protect lives across the globe.

An interview with Alan Dangour

Matthew Boyer for Mongabay: Can you share a bit about your background and what led you to your current role at the Wellcome Trust?

Alan Dangour: I joined Wellcome in January 2022 to lead our Climate and Health program, which aims to put health at the heart of global climate action. Previously, I was a Professor of Food and Nutrition for Global Health at the London School of Hygiene and Tropical Medicine, working on the interconnections between environmental change, food systems and health. My years of research really highlighted to me the ways in which climate change not only affects the environment but also our health. Developing evidence-based solutions to the damage to our health done by climate change is genuinely vital.

Can you describe some of the key projects or initiatives the Wellcome Trust is currently funding in the area of climate and health?

Alan Dangour: We’re building evidence on the best course of action to tackle the health challenges caused by climate change. For example, the impact that extreme heat has on maternal health is well documented, but we currently lack detailed understanding of the biological mechanisms involved, and how to best reduce this risk to protect pregnant women. So, a priority area for Wellcome right now is to build understanding of the impacts of climate change on human health, which will be used to inform policymakers to drive positive change. This focus on real-life change is at the heart of all our climate and health research. We’re also supporting new approaches to synthesizing evidence  for climate and health using technology like AI. In the future, it would be amazing to have an open-access AI tool that automatically updates evidence syntheses as studies are published.

What are some of the biggest challenges you face in your efforts to address climate and health issues through philanthropy?

Alan Dangour: Tackling climate and health challenges requires experts from many different disciplines to work together, breaking down disciplinary silos. As a leader in the space, we have a role in challenging the current ways of working to stimulate more interdisciplinary research to solve these global challenges and to bring in different perspectives. We want to fund research that leads to action in the real world and offers practical solutions to address climate and health issues, so we aim to involve communities and policy stakeholders at every step of the way.

What opportunities do you see for philanthropy to make a significant impact in the climate and health sectors over the next decade?

Alan Dangour: Good climate action and health action often go hand in hand, and it would be great to see this recognized more frequently and explicitly. Research and policy in health need to factor in the impact of climate change to be resilient to the changes coming our way. Equally, when talking about the impact of climate change we need to move beyond measuring this in degrees Celsius, carbon emissions and sea level rises and start evaluating the climate crisis in terms of lives at risk and the work towards protecting them. Philanthropic organizations are in a unique position to help convene stakeholders from community groups to researchers to policy makers to help affect change.

What are the Wellcome Trust’s long-term goals for its climate and health initiatives?

Alan Dangour: We are working towards a healthier and more sustainable world where local communities and national governments are fully equipped to use evidence-based interventions to tackle climate and health emergencies.

For example, extreme heat can lead to heat exhaustion and heat stroke and can affect our ability to regulate our temperature, which puts a strain on our bodies and can be especially challenging for elderly populations, infants and those with chronic conditions. That’s why we’re supporting research teams to investigate different ways to manage and limit the health effects of heat in the communities that need it most. We’re funding research seeing if trees can protect agricultural workers from the long-term health risks associated with heat exposure. We also have a research group assessing the effectiveness of affordable, sunlight-reflecting cool-roof coatings on reducing the impact of extreme heat on vulnerable populations by keeping indoor temperatures cool. These are just some of the studies we’re funding to gather evidence and inform policy.

How do you incorporate the perspectives and needs of local communities into your climate and health projects?

Alan Dangour: It is vital that research involves stakeholders with deep local knowledge. This is to ensure that solutions are tailored to the unique challenges that people face. For example, research we fund at the Zvitambo Institute for Maternal and Child Health Research in Zimbabwe is working very closely with local communities to not only understand the effects of climate change on child malnutrition but also how a community-driven response can help to address this.

How does the Wellcome Trust ensure that its climate and health initiatives promote global health equity?

Alan Dangour: We don’t want our funded research to end simply in a scientific journal article. The findings have to help the people most affected by climate change. There are many different ways we try to ensure this.

For example, a lot of climate change and mental health research historically has been done in high income countries in the global north where vulnerabilities may differ and this means we don’t have the evidence or the understanding to develop effective interventions in other countries. Connecting Climate Minds, a Wellcome-funded project, has interviewed 900 experts around the world to better understand the intersection of climate change and mental health and identify research and policy priorities.

Access to data is a key element in advancing global health equity. We support the collection and sharing of data on climate and health to ensure that policymakers and scientists globally can access this evidence, so experts beyond those that we fund can leverage this information to develop practical and affordable solutions to climate change.

Regarding the intersection of climate and health, how might the constituency for addressing climate change be broadened with an emphasis on public health implications of higher temperatures and severe weather events?

Alan Dangour: Many people are still unaware of how climate change can impact their health, especially the health of those in vulnerable groups such as the elderly, the young and pregnant women.

We’re increasingly experiencing extreme heat and the spread of climate-sensitive infectious diseases such as dengue in areas where they have not historically been a major issue, further north in Europe and America, for example. While the speed at which this has happened is alarming, I am also hopeful that it will drive home the need to limit climate change and to develop health solutions.

What are some key lessons you’ve learned from your work that you think others in the field should be aware of?

Alan Dangour: I think that there are two key lessons that I’d like to share.  First that some of the most exciting and most innovative research occurs at the boundaries of existing disciplines coming together.  We’re bringing together the fields of global health and climate science – and it’s at the intersection of these disciplinary areas where the critical work needs to be done.  This does not come without challenges but when it works, and climate and health researchers work together with a shared goal the outputs are spectacular.  And secondly, that having a strong mission – and critically sticking to it – is essential and hugely motivating. Our mission to put health at the heart of climate change action has coalesced an exciting new global field and we’re already beginning to see the impacts!

Header image: Green rice paddies in Udomxai province, Laos. Photo by Rhett A. Butler

Matthew Boyer conducted the interview. Rhett A. Butler wrote the introduction.

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CHAPTER 6. Culture and demographics defines the Pan Amazon’s present

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Biology of Viruses and Viral Diseases

Viruses exact an enormous toll on the human population and are the single most important cause of infectious disease morbidity and mortality worldwide. Viral diseases in humans were first noted in ancient times and have since shaped our history. Scientific approaches to the study of viruses and viral disease began in the 19th century and led to the identification of specific disease entities caused by viruses. Careful clinical observations enabled the identification of many viral illnesses and allowed several viral diseases to be differentiated (e.g., smallpox vs. chickenpox and measles vs. rubella). Progress in an understanding of disease at the level of cells and tissues, exemplified by the pioneering work of Virchow, allowed the pathology of many viral diseases to be defined. Finally, the work of Pasteur ushered in the systematic use of laboratory animals for studies of the pathogenesis of infectious diseases, including those caused by viruses.

The first viruses were identified as the 19th century ended. Ivanovsky and Beijerinck identified tobacco mosaic virus, and Loeffler and Frosch discovered foot-and-mouth disease virus. These observations were quickly followed by the discovery of yellow fever virus and the seminal research on the pathogenesis of yellow fever by Walter Reed and the U. S. Army Yellow Fever Commission. 1 By the end of the 1930s, tumor viruses, bacteriophages, influenza virus, mumps virus, and many arthropod-borne viruses had been identified. This process of discovery has continued with growing momentum to the present, with recently identified skin cancer–associated Merkel cell polyomavirus, 2 novel Old World arenaviruses causing fatal disease, 3 , 4 bat-related respiratory coronavirus 5 and reoviruses, 6 , 7 and novel swine- and avian-origin influenza viruses 8 , 9 counted among the most recent entries in the catalog of human disease-causing viruses.

In the 1940s, Delbruck, Luria, and others 10 , 11 used bacteriophages as models to establish many basic principles of microbial genetics and molecular biology and identified key steps in viral replication. The pioneering experiments of Avery, MacLeod, and McCarty 12 on the transformation of pneumococci established DNA as the genetic material and set the stage for corroborating experiments by Hershey and Chase using bacteriophages. 13 In the late 1940s, Enders and colleagues 14 cultivated poliovirus in tissue culture. This accomplishment led to the development of both formalin-inactivated (Salk) 15 and live-attenuated (Sabin) 16 vaccines for polio and ushered in the modern era of experimental and clinical virology.

In recent years, x-ray crystallography has allowed visualization of virus structures at an atomic level of resolution. Nucleotide sequences of entire genomes of most human viruses are known, and functional domains of many viral structural and enzymatic proteins have been defined. This information is being applied to the development of new strategies to diagnose viral illnesses and design effective antiviral therapies. Techniques to detect viral genomes, such as the polymerase chain reaction (PCR) and its derivatives, have proven superior to conventional serologic assays and culture techniques for the diagnosis of many viral diseases. Nucleic acid–based strategies are now used routinely in the diagnosis of infections caused by enteroviruses, hepatitis B virus (HBV), hepatitis C virus (HCV), herpesviruses, human immunodeficiency virus (HIV), and, with increasing frequency, respiratory and enteric viral pathogens. Furthermore, rapid developments in mass spectrometry and nucleotide sequencing technology are permitting the application of these tools to highly sensitive and specific virus detection in clinical specimens.

Perhaps an even more exciting development is the means to introduce new genetic material into viral genomes. Strategies now exist whereby specific mutations or even entire genes can be inserted into the genomes of many viruses. Such approaches can be exploited in the rational design of vaccines and the development of viral vectors for use in gene delivery. Furthermore, these powerful new techniques are leading to breakthroughs in foundational problems in viral pathogenesis, such as the nature of virus–cell interactions that produce disease, immunoprotective and immunopathologic host responses to infection, and viral and host determinants of contagion. Improved understanding of these aspects of viral infection will facilitate new approaches to the prevention, diagnosis, and treatment of viral diseases.

Virus Structure and Classification

The first classification of viruses as a group distinct from other microorganisms was based on the capacity to pass through filters of a small pore size (filterable agents). Initial subclassifications were based primarily on pathologic properties such as specific organ tropism (e.g., hepatitis viruses) or common epidemiologic features such as transmission by arthropod vectors (e.g., arboviruses). Current classification systems are based on the following: (1) the type and structure of the viral nucleic acid and the strategy used in its replication; (2) the type of symmetry of the virus capsid (helical vs. icosahedral); and (3) the presence or absence of a lipid envelope ( Table 134-1 ).

TABLE 134-1

Classification of Viruses

(+), message sense; (−), complement of message sense; DS, double-stranded; H, helical; I, icosahedral; S, spherical; SS, single-stranded.

Virus particles—virions—can be functionally conceived as a delivery system that surrounds a payload. The delivery system consists of structural components used by the virus to survive in the environment and bind to host cells. The payload contains the viral genome and often includes enzymes required for the initial steps in viral replication. In almost all cases, the delivery system must be removed from the virion to allow viral replication to commence.

In addition to mediating attachment to host cells, the delivery system also plays a crucial role in determining the mode of transmission between hosts. Viruses containing lipid envelopes are sensitive to desiccation in the environment and, for the most part, are transmitted by the respiratory, parenteral, and sexual routes. Nonenveloped viruses are stable to harsh environmental conditions and are often transmitted by the fecal-oral route.

Viral genomes exist in a variety of forms and sizes and consist of RNA or DNA (see Table 134-1 ). Animal virus genomes range in size from 3 kb, encoding only three or four proteins in small viruses such as the hepadnaviruses, to more than 300 kb, encoding several hundred proteins in large viruses such as the poxviruses. Viral genomes are single- or double-stranded and circular or linear. RNA genomes are composed of a single molecule of nucleic acid or multiple discrete segments, which can vary in number from as few as two in the arenaviruses up to 12 in some members of the Reoviridae. Viral nucleic acid is packaged in a protein coat, or capsid, that consists of multiple protein subunits. The combination of the viral nucleic acid and the surrounding protein capsid is often referred to as the nucleocapsid ( Fig. 134-1 ).

Schematic diagrams illustrating the structure of a nonenveloped icosahedral virus (A) and an enveloped helical virus (B). Nucleocapsid: combination of a viral nucleic acid and surrounding protein capsid.

Structural details of many viruses have now been defined at an atomic level of resolution ( Fig. 134-2 ). General features of virus structure can be gained from examination of electron micrographs of negatively stained virions and thin-section electron micrographs of virus-infected tissues and cultured cells. These techniques allow rapid identification of viral size, shape, symmetry, and surface features, presence or absence of an envelope, and intracellular site of viral assembly. Cryoelectron microscopy and computer image processing techniques are used to determine the three-dimensional structures of spherical viruses at a level of resolution far superior to that of negatively stained electron micrographs. A major advantage of cryoelectron microscopy is that it allows structural studies of viruses to be performed under conditions that do not alter native virion structure. Moreover, recent advances in cryoelectron microscopy have extended the achievable resolution of particle-associated proteins to near-atomic levels, sufficient to recognize characteristic features of secondary structural elements. 17 Image reconstructions of cryoelectron micrographs, sometimes in combination with x-ray crystallography, can also be used to investigate structural aspects of various virus functions, including receptor binding 18 , 19 , 20 and interaction with antibodies. 21 , 22 Identification of key motifs, such as receptor binding sites or immunodominant domains, provides the framework for understanding the structural basis of virus–cell interactions. Electron tomography with image reconstruction has been applied to architectural studies of viruses and intracellular foci of virus replication, rendering exquisite three-dimensional representations of particle organization and revealing the structure and subcellular origins of virus manufacturing centers. 23 , 24

Structural studies of poliovirus.

A, Negative-stained electron micrograph. B, Three-dimensional image reconstruction of cryoelectron micrographs. C, Structure determined by x-ray crystallography.

A number of general principles have emerged from studies of virus structure. In almost all cases, the capsid is composed of a repeating series of structurally similar subunits, each of which in turn is composed of only a few different proteins. The parsimonious use of structural proteins in a repetitive motif minimizes the amount of genetic information required to encode the viral capsid and leads to structural arrangements with symmetrical features. All but the most complex viruses exhibit either helical or icosahedral symmetry (see Table 134-1 ). Viruses with helical symmetry contain repeating protein subunits bound at regular intervals along a spiral formed by the viral nucleic acid. Interestingly, all known animal viruses that show this type of symmetry have RNA genomes. Viruses with icosahedral symmetry display twofold, threefold, and fivefold axes of rotational symmetry, and viral nucleic acid is intimately associated with specific capsid proteins in an ordered packing arrangement.

The use of repeating subunits with symmetrical protein-protein interactions facilitates the assembly of the viral capsid. In most cases, viral assembly appears to be a spontaneous process that occurs under the appropriate physiologic conditions and often can be reproduced when recombinant viral proteins are expressed in the absence of viral replication. 25 , 26 For many viruses, assembly of the capsid proceeds through a series of intermediates, each of which nucleates the addition of subsequent components in the assembly sequence.

One of the most poorly understood aspects of viral assembly is the process that ensures that the viral nucleic acid is correctly packaged into the capsid. In the case of viruses with helical symmetry, there may be an initiation site on the nucleic acid to which the initial capsid protein subunit binds, triggering the addition of subsequent subunits. The genomes of most DNA-containing viruses are inserted into preassembled capsid intermediates (procapsids) through adenosine triphosphate–driven mechanisms. 27 In preparations of many icosahedral viruses, empty capsids (i.e., capsids lacking nucleic acid) are frequently observed, indicating that assembly may proceed to completion without a requirement for the viral genome.

In some viruses, the nucleocapsid is surrounded by a lipid envelope acquired as the virus particle buds from the host cell cytoplasmic, nuclear, or endoplasmic reticular membrane (see Fig. 134-1 ). Inserted into this lipid bilayer are virus-encoded proteins (e.g., the hemagglutinin [HA] and neuraminidase proteins of influenza virus and gp41 and gp120 of HIV), which are exposed on the surface of the virus particle. These viral proteins usually contain a glycosylated hydrophilic external portion and internal hydrophobic domains that span the lipid membrane and anchor the protein into the viral envelope. In some cases, another viral protein, often termed a matrix protein, associates with the internal (cytoplasmic) surface of the lipid envelope, where it can interact with the cytoplasmic domains of the envelope glycoproteins. Matrix proteins may play roles in stabilizing the interaction between viral glycoproteins and the lipid envelope, directing the viral genome to intracellular sites of viral assembly, or facilitating viral budding. Matrix proteins can also influence a diverse set of cellular functions, such as inhibition of host cell transcription 28 , 29 and evasion of the cellular innate antiviral response. 30

Virus–Cell Interactions

Viruses require an intact cell to replicate and can direct the synthesis of hundreds to thousands of progeny viruses during a single cycle of infection. In contrast to other microorganisms, viruses do not replicate by binary fission. Instead, the infecting particle must disassemble in order to direct synthesis of viral progeny.

The interaction between a virus and its host cell begins with attachment of the virus particle to specific receptors on the cell surface. Viral proteins that mediate the attachment function (viral attachment proteins) include the following: single-capsid components that extend from the virion surface, such as the attachment proteins of adenovirus, 31 reovirus, 32 and rotavirus 33 , 34 ; surface glycoproteins of enveloped viruses, such as influenza virus 35 , 36 ( Fig. 134-3 ) and HIV 37 , 38 ; viral capsid proteins that form binding pockets that engage cellular receptors, such as the canyon formed by the capsid proteins of poliovirus 39 and rhinovirus 40 ; and viral capsid proteins that contain extended loops capable of binding receptors, such as foot-and-mouth disease virus. 41 Studies of the attachment of several diverse virus groups, including adenoviruses, coronaviruses, herpesviruses, lentiviruses, and reoviruses, indicate that multiple interactions between virus and cell occur during the attachment step. These observations indicate that a specific sequence of binding events between virus and cell optimizes specificity and contributes significant stability to the association. 42

The folded structure of the influenza virus hemagglutinin (HA) and its rearrangement when exposed to low pH.

A, The HA monomer. HA1 is blue, and HA2 is multicolored. The receptor-binding pocket resides in the virion-distal portion of HA1. The viral membrane would be at the bottom of this figure. B, Conformational change in HA induced by exposure to low pH. Note the dramatic structural rearrangement in HA2, in which amino acid residues 40-105 become a continuous alpha helix. Dashed lines indicate regions of undetermined structure. This model of HA in its fusion conformation is a composite of the HA1 domain structure and the low-pH HA2 structure.

One of the most dynamic areas of virology concerns the identification of virus receptors on host cells. This interest stems in part from the critical importance of the attachment step as a determinant of target cell selection by many viruses. Several virus receptors have now been identified ( Table 134-2 ), and three important principles have emerged from studies of these receptors. First, viruses have adapted to use cell surface molecules designed to facilitate a variety of normal cellular functions. Virus receptors may be highly specialized proteins with limited tissue distribution, such as complement receptors, growth factor receptors, or neurotransmitter receptors, or more ubiquitous components of cellular membranes, such as integrins and other intercellular adhesion molecules, glycosaminoglycans, or sialic acid–containing oligosaccharides. Second, many viruses use more than a single receptor to mediate multistep attachment and internalization. For example, adenovirus binds coxsackievirus and adenovirus receptor (CAR) 43 and the integrins α v β 3 or α v β 5 44 ; herpes simplex virus (HSV) binds heparan sulfate 45 , 46 , 47 and herpesvirus entry mediator (HVEM/HveA), 48 nectin 1 (PRR1/HveC), 49 or nectin 2 (PRR2/HveB) 50 ; HIV binds CD4 51 , 52 and chemokine receptors CXCR4 53 , 54 or CCR5 55 , 56 , 57 ; and reovirus binds sialylated glycans 58 , 59 and JAM-A. 60 , 61 Third, in many cases, receptor expression is not the sole determinant of viral tropism for particular cells and tissues in the host. Therefore, although receptor binding is the first step in the interaction between virus and cell, subsequent events in the viral replication cycle must also be supported for productive viral infection to occur.

TABLE 134-2

Receptors and Entry Mediators Used by Selected Human Viruses

Several viruses bind receptors expressed at regions of cell-cell contact. 62 Junctional adhesion molecule-A (JAM-A), which serves as a receptor for reovirus 60 and feline calicivirus, 63 and CAR, which serves as a receptor for some coxsackieviruses and adenoviruses, 43 are expressed at tight junctions 64 , 65 and adherens junctions. 66 , 67 Junctional regions are sites of enhanced membrane recycling, endocytic uptake, and intracellular signaling. 68 Therefore, it is possible that viruses have selected junction-associated proteins as receptors to usurp the physiologic functions of these molecules. In this regard, interactions of coxsackievirus with decay-accelerating factor elicit a tyrosine kinase–based signaling cascade that mediates subsequent interactions of the virus with CAR in tight junctions. 69 Structures of viral proteins or whole viral particles in complex with sialic acid have been determined for some viruses, including the influenza virus hemagglutinin (HA) 36 , 70 (see Fig. 134-3 ), polyomavirus, 71 , 72 , 73 , 74 foot-and-mouth disease virus, 75 reovirus attachment protein σ1, 58 , 59 and the VP8 domain of rotavirus capsid protein VP4. 34 Sialic acid binding in each of these cases occurs in a shallow groove at the surface of the viral protein. However, the architectures of the binding sites differ. Structures of complexes of viral proteins or viral particles and cell surface protein receptors have also been determined. These include adenovirus fiber knob and CAR, 76 Epstein-Barr virus (EBV) gp42 and major histo­compatibility complex (MHC) class II protein, 77 HSV glycoprotein D and HVEM/HveA, 78 HIV gp120 and CD4, 38 measles virus HA and CD46 79 and SLAM (signaling lymphocyte-activation molecule), 80 reovirus σ1 and JAM-A, 61 and rhinovirus and ICAM-1 (intercellular adhesion molecule 1). 81 In several of these cases, the viral attachment proteins engage precisely the same domains used by their cognate receptors to bind natural ligands.

Penetration and Disassembly

Once attachment has occurred, the virus must penetrate the cell membrane, and the capsid must undergo a series of disassembly steps (uncoating) that prepare the virus for the next phases in viral replication. Enveloped viruses such as the paramyxoviruses and retroviruses enter cells by fusion of the viral envelope with the cell membrane ( Fig. 134-4 ). Attachment of these viruses to the cell surface induces changes in viral envelope proteins required for membrane fusion. For example, the binding of CD4 and certain chemokine receptors by HIV envelope glycoprotein gp120 induces a series of conformational changes in gp120 that lead to the exposure of transmembrane protein gp41. 82 , 83 Fusion of viral and cellular membranes proceeds through subsequent interactions of the hydrophobic gp41 fusion peptide with the cell membrane. 84 , 85 , 86 , 87

Mechanisms of viral entry into cells.

Nonenveloped (A) and enveloped (B) virus internalization by receptor-mediated endocytosis.

Other viruses enter cells by some form of receptor-mediated endocytic uptake (see Fig. 134-4 ). For several viruses, virus–receptor complexes induce formation of clathrin-coated pits that invaginate from the cell membrane to form coated vesicles. 88 These vesicles are rapidly uncoated and fuse with early endosomes, which sort internalized proteins for recycling to the cell surface or other cellular compartments, such as late endosomes or lysosomes. For other viruses, virus–receptor complexes are taken into cells by caveolae in lipid rafts. 88 Enveloped viruses such as dengue virus, 89 influenza virus, 90 and Semliki Forest virus 91 exploit the acidic environment of the endocytic compartment to induce conformational changes in surface glycoproteins required for membrane fusion. High-resolution structures of the influenza virus HA at acidic pH illustrate a dramatic conformational alteration leading to the fusion-active state (see Fig. 134-3 ). 90

Endocytic uptake and acidification are also required for entry of some nonenveloped viruses such as adenovirus, 92 , 93 parvovirus, 94 and reovirus. 95 , 96 In these cases, acidic pH may facilitate disassembly of the viral capsid to enable subsequent penetration of endosomal membranes. In addition to acidic pH, endocytic cathepsin proteases are required for disassembly of several viruses, including Ebola virus, 97 Hendra virus, 98 reovirus, 99 and severe acute respiratory syndrome (SARS) coronavirus. 100

In contrast to enveloped viruses, nonenveloped viruses cross cell membranes using mechanisms that do not involve membrane fusion. This group of viruses includes several human pathogens, with adenoviruses, picornaviruses, and rotaviruses serving as prominent examples. Despite differences in genome and capsid composition, each of these viruses must penetrate cell membranes to deliver the genetic payload to the interior of the cell. Capsid rearrangements triggered by receptor binding, 101 , 102 acidic pH, 92 , 93 or proteolysis 103 , 104 serve essential functions in membrane penetration by some nonenveloped viruses. Although a precise understanding of the biochemical mechanisms that underlie viral membrane penetration is incomplete, small capsid proteins of several nonenveloped viruses, such as adenovirus, 105 poliovirus, 106 and reovirus, 107 are required for membrane penetration, perhaps by forming pores in host cell membranes.

Genome Replication

Once a virus has entered a target cell, it must replicate its genome and proteins. Replication strategies used by single-stranded RNA-containing viruses depend on whether the genome can be used as messenger (m)RNA. Translation-competent genomes, which include those of the coronaviruses, flaviviruses, picornaviruses, and togaviruses, are termed plus (+) sense and are translated by cellular ribosomes immediately following entry of the genome into the cytoplasm. For most viruses containing (+) sense RNA genomes, translation results in the synthesis of a large polyprotein that is cleaved into several smaller proteins through the action of viral and sometimes host proteases. One of these proteins is an RNA-dependent RNA polymerase (RdRp), which replicates the viral RNA. Genome replication of (+) sense RNA-containing viruses requires synthesis of a minus (–) sense RNA intermediate, which serves as template for production of (+) sense genomic RNA.

A different strategy is used by viruses containing (−) sense RNA genomes. The genomes of these viruses, which include the filoviruses, orthomyxoviruses, paramyxoviruses, and rhabdoviruses, cannot serve directly as mRNA. Therefore, viral particles must contain a co-packaged RdRp to transcribe (+) sense mRNAs using the (−) sense genomic RNA as template. Genome replication of (−) sense RNA-containing viruses requires synthesis of a (+) sense RNA intermediate, which serves as a template for production of (−) sense genomic RNA. Mechanisms that determine whether (+) sense RNAs are used as templates for translation or genome replication are not well understood.

RNA-containing viruses belonging to the family Reoviridae have segmented double-stranded (ds) RNA genomes. The innermost protein shell of these viruses (termed a single-shelled particle or core ) contains an RdRp that catalyzes the synthesis of (+) sense mRNA using as a template the (−) sense strand of each dsRNA segment. The mRNAs of these viruses are capped at their 5′-termini by virus-encoded enzymes and then extruded into the cytoplasm through channels in the single-shelled particle. 108 The (+) sense mRNAs also serve as a template for replication of dsRNA gene segments. Viral genome replication is thus completely conservative; neither strand of parental dsRNA is present in newly formed genomic segments.

The retroviruses are RNA-containing viruses that replicate using a DNA intermediate. The viral genomic RNA is (+) sense and single stranded; however, it does not serve as mRNA following viral entry. Instead, the retrovirus RNA genome is a template for synthesis of a double-stranded DNA copy, termed the provirus. Synthesis of the provirus is mediated by a virus-encoded RNA-dependent DNA polymerase or reverse transcriptase, so named because of the reversal of genetic information from RNA to DNA. The provirus translocates to the nucleus and integrates into host DNA. Expression of this integrated DNA is regulated for the most part by cellular transcriptional machinery. However, the human retroviruses HIV and human T-cell leukemia virus (HTLV) encode proteins that augment transcription of viral genes. Intracellular signaling pathways are capable of activating retroviral gene expression and play important roles in inducing high levels of viral replication in response to certain stimuli. 109 Transcription of the provirus yields mRNAs that encode viral proteins and genome-length RNAs that are packaged into progeny virions. Such a replication strategy results in persistent infection in the host because the viral genome is maintained in the host cell genome and replicated with each cell division.

With the exception of the poxviruses, viruses containing DNA genomes replicate in the nucleus and for the most part use cellular enzymes for transcription and replication of their genomes. Transcription of most DNA-containing viruses is tightly regulated and results in the synthesis of early and late mRNA transcripts. The early transcripts encode regulatory proteins and proteins required for DNA replication, whereas the late transcripts encode structural proteins. Several DNA-containing viruses, such as adenovirus and human papillomavirus (HPV), induce cells to express host proteins required for viral DNA replication by stimulating cell-cycle progression. For example, the HPV E7 protein binds the retinoblastoma gene product pRB and liberates transcription factor E2F, which induces the cell cycle. 110 , 111 To prevent programmed cell death in response to E7-mediated unscheduled cell cycle progression, the HPV E6 protein mediates the ubiquitylation and degradation of tumor suppressor protein p53. 112 , 113 , 114

Some DNA-containing viruses, such as the herpesviruses, can establish latent infections in the host. Unlike the retroviruses, genomes of the herpesviruses do not integrate into host chromosomes but instead exist as plasmid-like episomes. Mechanisms that govern establishment of latency and subsequent reactivation of replication are not well understood. However, microRNAs encoded by cytomega­lovirus (CMV) and perhaps other herpesviruses may promote persistence by targeting viral and cellular mRNAs that control viral gene expression and replication and innate immune responses to viral infection. 115 , 116

A fascinating aspect of virus–cell interactions is the replication microenvironments established in infected cells. Viral replication is a sophisticated interplay of transcription, translation, nucleic acid amplification, and particle assembly. Furthermore, infection must proceed under sensitive pathogen surveillance systems trained on virus-associated molecular patterns (e.g., unmethylated CpG dinucleotides in DNA viral genomes) and replicative intermediates (e.g., dsRNA generated during RNA virus replication) that may impose impassable blocks to infection. 117 Partitioning of the viral replication machinery from the surrounding intracellular milieu satisfies a spatial requirement to concentrate viral proteins and nucleic acid for efficient genome amplification and encapsidation while simultaneously shielding viral products from cellular sensors that provoke antiviral innate immune responses. Hence, as a rule, viral replication is a localized process, occurring within morphologically discrete cytoplasmic or nuclear structures variously termed viral inclusions (or inclusion bodies ), virosomes, viral factories, or viroplasm. These entities are novel, metabolically active organelles formed by contributions from both virus and cell. Many highly recognizable features of viral cytopathic effect observed using light microscopy, such as dense nuclear inclusions or refractile cytoplasmic densities, represent locally concentrated regions of viral nucleic acid and protein.

Membrane-associated replicase complexes appropriated by (+) sense RNA viruses are perhaps the most conspicuous examples of compartmentalized viral replication. In cells infected by these viruses, intracellular membranes originating from the endoplasmic reticulum (ER; e.g., picornaviruses 118 , 119 ), ER-Golgi intermediate compartment and trans -Golgi network (e.g., flaviviruses 120 ), endolysosomal vesicles (e.g., alphaviruses 121 ), and autophagic vacuoles (e.g., poliovirus 122 ) are reduplicated and reorganized by viral proteins into platforms that anchor viral replication complexes consisting of the RdRp and other RNA-modifying enzymes necessary for RNA synthesis. Curiously, dsRNA viruses are thought to generate nonmembranous intracytoplasmic replication factories, even though their life cycles pass through a (+) polarity RNA intermediate. However, in an interesting functional parallel with (+) sense RNA viruses, the assembly pathway of rotavirus, a dsRNA virus, involves budding of immature particles into the ER, where a lipid envelope is transiently acquired and subsequently replaced by the outermost protein shell. 123 Perhaps additional roles for cellular membranes in non–membrane-bound viral replication complexes await discovery.

The tight relationship of RNA virus replication to cellular membranes is less predictable for DNA viruses. For example, in distinction to the supporting role of autophagy in the replication of some RNA viruses, autophagosomes (stress-induced, double-membraned vesicles that remove noxious cytoplasmic materials to lysosomes for degradation) defend against infection by HSV-1, which encodes a protein that inhibits induction of autophagy and accentuates viral virulence. 124 , 125 The replication and assembly complexes of many DNA viruses, including adenoviruses, herpesviruses, papillomaviruses, polyomaviruses, and parvoviruses, are associated with promyelocytic leukemia (PML) nuclear bodies, 126 , 127 which have been ascribed functions in diverse nuclear processes encompassing gene regulation, tumor suppression, apoptosis, and removal of aggregated or foreign proteins. 128 It appears that DNA viruses exploit PML bodies in a variety of ways, which include consolidation and disposal of misfolded viral proteins, sequestration of host-cell stress response factors that block infection, and segregation of interfering cellular DNA repair proteins from sites of viral replication. 129

The life cycles of all viruses that replicate in eukaryotic cells are physically and functionally intertwined with the cytoskeleton. Many viruses with nuclear replication programs, such as adenovirus, HSV, and influenza virus, are transported by motor proteins along micro­tubules toward the nucleus, resulting ultimately in release of the viral genome into the nucleoplasm through nuclear pores. 130 The micro­tubule network is also conscripted as an egress pathway by a number of enveloped viruses (e.g., HIV, HSV, vaccinia virus) for conveyance of immature particles to cytolemmal sites of virion budding. 131 Furthermore, microtubules and actin filaments may serve as anchorage points for nucleoprotein complexes that coordinate genome expression or replication with cytoplasmic replication programs, exemplified by parainfluenza virus (PIV), 132 reovirus, 133 and vaccinia virus. 134 Because the cytoskeleton is a decentralized organelle linking cellular structural elements to the metabolic and transport machineries, it is not surprising that viruses capitalize on this highly integrative system, which provides a stable platform for replication and enables purposeful movement of virions or subviral components within cells to facilitate the requisite partitioning of viral assembly and disassembly.

Cell Killing

Viral infection can compromise numerous cellular processes, such as nucleic acid and protein synthesis, maintenance of cytoskeletal architecture, and preservation of membrane integrity. 135 Many viruses are also capable of inducing the genetically programmed mechanism of cell death that leads to apoptosis of host cells. 136 , 137 Apoptotic cell death is characterized by cell shrinkage, membrane blebbing, condensation of nuclear chromatin, and activation of an endogenous endonuclease, which results in cleavage of cellular DNA into oligonucleosome-length DNA fragments. 138 These changes occur according to predetermined developmental programs or in response to certain environmental stimuli. In some cases, apoptosis may serve as an antiviral defense mechanism to limit viral replication by destruction of virus-infected cells or reduction of potentially harmful inflammatory responses elicited by viral infection. 139 In other cases, apoptosis may result from viral induction of cellular factors required for efficient viral replication. 136 , 137 Generally, RNA-containing viruses, including influenza virus, measles virus, poliovirus, reovirus, and Sindbis virus, induce apoptosis of host cells, whereas DNA-containing viruses, including adenovirus, CMV, EBV, HPV, and the poxviruses, encode proteins that block apoptosis. For some viruses, the duration of the viral infectious cycle may determine whether apoptosis is induced or inhibited. Viruses capable of completing an infectious cycle before induction of apoptosis would not require a means to inhibit this cellular response to viral infection. Interestingly, several viruses that cause encephalitis are capable of inducing apoptosis of infected neurons ( Fig. 134-5 ). 140 , 141 , 142

Reovirus-induced apoptosis in the murine central nervous system.

Consecutive sections of the hippocampus prepared from a newborn mouse 10 days following intracranial inoculation with reovirus strain type 3 Dearing. Cells were stained with (A) hematoxylin and eosin, (B) reovirus antigen, and (C) the activated form of apoptosis protease caspase-3. Cells that stain positive for reovirus antigen or activated caspase 3 contain a dark precipitate in the cytoplasm, including neuronal processes. Scale bars, 100 µm.

Antiviral Drugs

(Also see Chapters 43 to 47Chapter 43Chapter 44Chapter 45Chapter 46Chapter 47.)

Knowledge of viral replication strategies has provided insights into critical steps in the viral life cycle that can serve as potential targets for antiviral therapy. For example, drugs can be designed to interfere with virus binding to target cells or prevent penetration and disassembly once receptor engagement has occurred. Steps involved in the replication of the viral genome are also obvious targets for antiviral therapy. A number of antiviral agents inhibit viral polymerases, including those active against herpesviruses (e.g., acyclovir), HIV (e.g., zidovudine), and HBV (e.g., entecavir). Drugs that inhibit viral proteases have been developed; several are used to treat HCV 143 , 144 and HIV 145 infection. These drugs block the proteolytic processing of viral precursor polyproteins and serve as potent inhibitors of replication. Other viral enzymes also serve as targets for antiviral therapy. The influenza virus neuraminidase is required for the release of progeny influenza virus particles from infected cells. Oseltamivir and zanamivir bind the neuraminidase catalytic site and efficiently inhibit the enzyme. 146 These drugs have been used in the prophylaxis and treatment of influenza virus infection. 147

Better understanding of viral replication strategies and mechanisms of virus-induced cell killing is paving the way for the rational design of novel antiviral therapeutics. One of the most exciting approaches to the development of antiviral agents is the use of high-resolution x-ray crystallography and molecular modeling to optimize interactions between these inhibitory molecules and their target viral proteins. Such structure-based drug design has led to the development of synthetic peptides (e.g., enfuvirtide) that inhibit HIV entry by blocking gp41-mediated membrane fusion. 148 Other vulnerable steps in HIV replication are targets of drugs approved for patient treatment, including entry inhibitors that interfere with gp120 binding to CCR5 149 and agents that prevent proviral integration into cellular DNA through inhibition of viral integrase activity 150 (see Chapter 130). Several inhibitors of the HCV protease and polymerase are also in clinical development 151 (see Chapter 46).

Despite promising advances in rational antiviral drug design, current therapeutic approaches to some viral infections rely heavily on compounds with less specific mechanisms of action. One such agent, interferon (IFN)-α, efficiently inhibits a broad spectrum of viruses and is secreted by diverse cell types as part of the host innate immune response. Recombinant IFN-α is presently used to treat HBV and HCV infections. Ribavirin, a synthetic guanosine analogue, inhibits the replication of many RNA- and DNA-containing viruses through complex mechanisms involving inhibition of viral RNA synthesis and disturbances in intracellular pools of guanosine triphosphate. 152 , 153 This drug is routinely used to treat HCV infection and sometimes administered in aerosolized form to treat respiratory syncytial virus (RSV) lower respiratory tract infection in hospitalized children and in severely ill and immunocompromised patients. Ribavirin therapy reduces the mortality associated with certain viral hemorrhagic fevers, such as that caused by Lassa virus. 154 Broader-spectrum therapies exemplified by IFN-α and ribavirin remain part of the first-line defense against emerging pathogens and other susceptible viruses for which biochemical and structural information is insufficient to design high-potency agent-specific drugs.

Virus–Host Interaction

One of the most formidable challenges in virology is to apply knowledge gained from studies of virus–cell interactions in tissue culture systems to an understanding of how viruses interact with host organisms to cause disease. Virus–host interactions are often described in terms of pathogenesis and virulence. Pathogenesis is the process whereby a virus interacts with its host in a discrete series of stages to produce disease ( Table 134-3 ). Virulence is the capacity of a virus to produce disease in a susceptible host. Virulence is often measured in terms of the quantity of virus required to cause illness or death in a predefined fraction of experimental animals infected with the virus. Virulence is dependent on viral and host factors and must be measured using carefully defined conditions (e.g., virus strain, dose, and route of inoculation; host species, age, and immune status). In many cases, it has been possible to identify roles played by individual viral and host proteins at specific stages in viral pathogenesis and to define the importance of these proteins in viral virulence.

TABLE 134-3

Stages in Virus–Host Interaction

The first step in the process of virus–host interaction is the exposure of a susceptible host to viable virus under conditions that promote infection ( Fig. 134-6 ). Infectious virus may be present in respiratory droplets or aerosols, in fecally contaminated food or water, or in a body fluid or tissue (e.g., blood, saliva, urine, semen, or a transplanted organ) to which the susceptible host is exposed. In some cases, the virus is inoculated directly into the host through the bite of an animal vector or through the use of a contaminated needle. Infection can also be transmitted from mother to infant through virus that has infected the placenta or birth canal or by virus in breast milk. In some cases, acute viral infections result from the reactivation of endogenous latent virus (e.g., reactivation of HSV giving rise to herpes labialis) rather than de novo exposure to exogenous virus.

Entry and spread of viruses in human hosts.

Some major steps in viral spread and invasion of target organs are shown. Neural spread is not illustrated. GI, gastrointestinal; HIV, human immunodeficiency virus; HPV, human papillomavirus.

Exposure of respiratory mucosa to virus by direct inoculation or inhalation is an important route of viral entry into the host. A simple cough can generate up to 10,000 small, potentially infectious aerosol particles, and a sneeze can produce nearly 2 million. The distribution of these particles depends on a variety of environmental factors, the most important of which are temperature, humidity, and air currents. In addition to these factors, particle size is an important determinant of particle distribution. In general, smaller particles remain airborne longer than larger ones. Particle size also contributes to particle fate after inhalation. Larger particles (>6 µm) are generally trapped in the nasal turbinates, whereas smaller particles may ultimately travel to the alveolar spaces of the lower respiratory tract.

Fecal-oral transmission represents an additional important route of viral entry into the host. Food, water, or hands contaminated by infected fecal material can facilitate the entry of a virus via the mouth into the gastrointestinal tract, the environment of which requires viruses that infect by this route to have certain physical properties. Viruses capable of enteric transmission must be acid stable and resistant to bile salts. Because conditions in the stomach and intestine are destructive to lipids contained in viral envelopes, most viruses that spread by the fecal-oral route are nonenveloped. Interestingly, many viruses that enter the host via the gastrointestinal tract require proteolysis of certain capsid components to infect intestinal cells productively. Treatment of mice with inhibitors of intestinal proteases blocks infection by reovirus 155 and rotavirus, 156 which demonstrates the critical importance of proteolysis in the initiation of enteric infection by these viruses. The host microbiota is essential for infection by some viruses. 157 , 158

To produce systemic disease, a virus must cross the mucosal barrier that separates the luminal compartments of the respiratory, gastrointestinal, and genitourinary tracts from the host's parenchymal tissues. Studies with reovirus illustrate one strategy used by viruses to cross mucosal surfaces to invade the host after entry into the gastrointestinal tract. 159 , 160 After oral inoculation of mice, reovirus adheres to the surface of intestinal microfold cells (M cells) that overlie collections of intestinal lymphoid tissue (Peyer's patches). In electron micrographs, reovirus virions can be followed sequentially as they are transported within vesicles from the luminal to the subluminal surface of M cells. Virions subsequently appear within Peyer's patches and then spread to regional lymph nodes and extraintestinal lymphoid organs such as the spleen. A similar pathway of spread has been described for poliovirus 161 and HIV, 162 suggesting that M cells represent an important portal for viral invasion of the host after entry into the gastrointestinal tract.

Once a virus has entered the host, it can replicate locally or spread from the site of entry to distant organs to produce systemic disease (see Fig. 134-6 ). Classic examples of localized infections in which viral entry and replication occur at the same anatomic site include respiratory infections caused by influenza virus, RSV, and rhinovirus; enteric infections produced by norovirus and rotavirus; and dermatologic infections caused by HPV (warts) and paravaccinia virus (milker's nodules). Other viruses spread to distant sites in the host after primary replication at sites of entry. For example, poliovirus spreads from the gastrointestinal tract to the central nervous system (CNS) to produce meningitis, encephalitis, or poliomyelitis. Measles virus and varicella-zoster virus (VZV) enter the host through the respiratory tract and then spread to lymph nodes, skin, and viscera. Pathobiologic definitions of viruses based on spread potential have begun to blur amid accumulating evidence that model agents of localized infection may disseminate to distant sites. For example, rotavirus, an important cause of pediatric acute gastroenteritis, replicates vigorously in villous tip epithelial cells of the small intestine but is also frequently associated with viral antigen and RNA in blood, the clinical significance of which is unclear. 163 Influenza virus is another case in point; viral RNA in blood is detected at a substantial frequency in hematopoietic cell transplant recipients and correlates with more severe disease and increased mortality. 164

Release of some viruses occurs preferentially from the apical or basolateral surface of polarized cells, such as epithelial cells. In the case of enveloped viruses, polarized release is frequently determined by preferential sorting of envelope glycoproteins to sites of viral budding. Specific amino-acid sequences in these viral proteins direct their transport to a particular aspect of the cell surface. 165 , 166 Polarized release of virus at apical surfaces may facilitate local spread of infection, whereas release at basolateral surfaces may facilitate systemic invasion by providing virus access to subepithelial lymphoid, neural, or vascular tissues.

Many viruses use the bloodstream to spread in the host from sites of primary replication to distant target tissues (see Fig. 134-6 ). In some cases, viruses may enter the bloodstream directly, such as during a blood transfusion or via an arthropod bite. More commonly, viruses enter the bloodstream after replication at some primary site. Important sites of primary replication preceding hematogenous spread of viruses include Peyer's patches and mesenteric lymph nodes for enteric viruses, bronchoalveolar cells for respiratory viruses, and subcutaneous tissue and skeletal muscle for alphaviruses and flaviviruses. In the case of reovirus, infection of endothelial cells leads to hematogenous dissemination in the host. 167 , 168

Pioneering studies by Fenner with mousepox (ectromelia) virus suggest that an initial low-titer viremia (primary viremia) serves to seed virus to a variety of intermediate organs, where a period of further replication leads to a high-titer viremia (secondary viremia) that disseminates virus to the ultimate target organs ( Fig. 134-7 ). 169 It is often difficult to identify primary and secondary viremias in naturally occurring viral infections. However, replication of many viruses in reticuloendothelial organs (e.g., liver, spleen, lymph nodes, bone marrow), muscle, fat, and even vascular endothelial cells can play an important role in maintaining viremia. 168

Pathogenesis of mousepox virus infection.

Successive waves of viremia are shown to seed the spleen and liver and then the skin.

Viruses that reach the bloodstream may travel free in plasma (e.g., enteroviruses and togaviruses) or in association with specific blood cells. 170 A number of viruses are spread hematogenously by macrophages (e.g., CMV, HIV, measles virus) or lymphocytes (e.g., CMV, EBV, HIV, HTLV, measles virus). Although many viruses have the capacity to agglutinate erythrocytes in vitro (a process called hemagglutination), only in exceptional cases (e.g., Colorado tick fever virus) are erythrocytes used to transport virus in the bloodstream.

The maintenance of viremia depends on the interplay among factors that promote virus production and those that favor viral clearance. A number of variables that affect the efficiency of virus removal from plasma have been identified. In general, the larger the viral particle, the more efficiently it is cleared. Viruses that induce high titers of neutralizing antibodies are more efficiently cleared than those that do not induce humoral immune responses. Finally, phagocytosis of virus by cells in the host reticuloendothelial system can contribute to viral clearance.

A major pathway used by viruses to spread from sites of primary replication to the nervous system is through nerves. Numerous diverse viruses, including Borna disease virus, coronavirus, HSV, poliovirus, rabies virus, reovirus, and Venezuelan equine encephalitis virus (VEE), are capable of neural spread. Several of these viruses accumulate at the neuromuscular junction after primary replication in skeletal muscle. 171 , 172 HSV appears to enter nerve cells via receptors that are located primarily at synaptic endings rather than on the nerve cell body. 173 Spread to the CNS by HSV, 174 rabies virus, 171 , 172 and reovirus 175 , 176 can be interrupted by scission of the appropriate nerves or by chemical agents that inhibit axonal transport. Neural spread of some of these viruses occurs by the microtubule-based system of fast axonal transport. 177

Viruses are not limited to a single route of spread. VZV, for example, enters the host by the respiratory route and then spreads from respiratory epithelium to the reticuloendothelial system and skin via the bloodstream. Infection of the skin produces the characteristic exanthem of chickenpox. The virus subsequently enters distal terminals of sensory neurons and travels to dorsal root ganglia, where it establishes latent infection. Reactivation of VZV from latency results in transport of the virus in sensory nerves to skin, where it gives rise to vesicular lesions in a dermatomal distribution characteristic of zoster or shingles .

Poliovirus is also capable of spreading by hematogenous and neural routes. Poliovirus is generally thought to spread from the gastrointestinal tract to the CNS via the bloodstream, although it has been suggested that the virus may spread via autonomic nerves in the intestine to the brainstem and spinal cord. 178 , 179 This hypothesis is supported by experiments using transgenic mice expressing the human poliovirus receptor. 180 When these mice are inoculated with poliovirus intramuscularly in the hind limb, virus does not reach the CNS if the sciatic nerve ipsilateral to the site of inoculation is transected. 181 Once poliovirus reaches the CNS, axonal transport is the major route of viral dissemination. Similar mechanisms of spread may be used by other enteroviruses.

The capability of a virus to infect a distinct group of cells in the host is referred to as tropism. For many viruses, tropism is determined by the availability of virus receptors on the surface of a host cell. This concept was first appreciated in studies of poliovirus when it was recognized that the capacity of the virus to infect specific tissues paralleled its capacity to bind homogenates of the susceptible tissues in vitro. 182 The importance of receptor expression as a determinant of poliovirus tropism was conclusively demonstrated by showing that cells not susceptible for poliovirus replication could be made susceptible by recombinant expression of the poliovirus receptor. 183 In addition to the availability of virus receptors, tropism can also be determined by postattachment steps in viral replication, such as the regulation of viral gene expression. For example, some viruses contain genetic elements, termed enhancers, that act to stimulate transcription of viral genes. 184 , 185 Some enhancers are active in virtually all types of cells, whereas others show exquisite tissue specificity. The promoter-enhancer region of John Cunningham (JC) polyomavirus is active in cultured human glial cells but not in HeLa cervical epithelial cells. 186 Cell-specific expression of the JC virus genome correlates well with the capacity of this virus in immunocompromised persons to produce progressive multifocal leukoencephalopathy, a disease in which JC virus infection is limited to oligodendroglia in the CNS.

Specific steps in virus–host interaction, such as the route of entry and pathway of spread, also can strongly influence viral tropism. For example, encephalitis viruses such as VEE are transmitted to humans by insect bites. These viruses undergo local primary replication and then spread to the CNS by hematogenous and neural routes. 187 After oral inoculation, VEE is incapable of primary replication and spread to the CNS, illustrating that tropism can be determined by the site of entry into the host. Influenza virus buds exclusively from the apical surface of respiratory epithelial cells, 188 which may limit its capacity to spread within the host and infect cells at distant sites.

A wide variety of host factors can influence viral tropism. These include age, nutritional status, and immune responsiveness, as well as certain genetic polymorphisms that affect susceptibility to viral infection. Age-related susceptibility to infection is observed for many viruses, including reovirus, 189 , 190 RSV, 191 , 192 , 193 and rotavirus. 194 , 195 The increased susceptibility in young children to these viruses may in part be due to immaturity of the immune response but also may be related to intrinsic age-specific factors that enhance host susceptibility to infection. Nutritional status is a critical determinant of the tropism and virulence of many viruses. For example, persons with vitamin A deficiency have enhanced susceptibility to measles virus infection. 196 , 197 Similarly, the outcome of most viral infections is strongly linked to the immune competence of the host.

The genetic basis of host susceptibility to viral infections is complex. Studies with inbred strains of mice indicate that genetic variation can alter susceptibility to viral disease by a variety of mechanisms. 198 These can involve differences in immune responses, variability in the ability to produce antiviral mediators such as IFN, and differential expression of functional virus receptors. Polymorphisms in the expression of chemokine receptor CCR5, which serves as a co-receptor for HIV, 55 , 56 , 57 are associated with alterations in susceptibility to HIV infection. 199 , 200

Persistent Infections

Many viruses are capable of establishing persistent infections, of which two types are recognized: chronic and latent. Chronic viral infections are characterized by continuous shedding of virus for prolonged periods of time. Congenital infections with rubella virus and CMV and persistent infections with HBV and HCV are examples of chronic viral infections. Latent viral infections are characterized by maintenance of the viral genome in host cells in the absence of viral replication. Herpesviruses and retroviruses can establish latent infections. The distinction between chronic and latent infections is not readily apparent for some viruses, such as HIV, which can establish both chronic and latent infections in the host. 201 , 202 , 203 Viruses capable of establishing persistent infections must have a means of evading the host immune response and a mechanism of attenuating their virulence. Lentiviruses such as equine infectious anemia virus 204 and HIV 205 , 206 , 207 are capable of extensive antigenic variation resulting in escape from neutralizing antibody responses by the host.

Several viruses encode proteins that directly attenuate the host immune response (e.g., the adenovirus E3/19K protein 208 and CMV US11 gene product 209 block cell surface expression of MHC class I proteins, resulting in diminished presentation of viral antigens to cytotoxic T lymphocytes [CTLs]). The poxviruses encode a variety of immunomodulatory molecules including CrmA, which blocks T-cell–mediated apoptosis of virus-infected cells. 210 In some cases (e.g., the CNS), preferential sites for persistent viral infections are not readily accessible by the immune system, 211 which may favor establishment of persistence.

Viruses and Cancer

Several viruses produce disease by promoting malignant transformation of host cells. Work by Peyton Rous with an avian retrovirus was the first to demonstrate that viral infections can cause cancer. 212 Rous sarcoma virus encodes an oncogene, v -src, which is a homologue of a cellular proto-oncogene, c -src. 213 , 214 Cells infected with Rous sarcoma virus become transformed. 215 , 216 , 217 , 218 , 219 Several viruses are associated with malignancies in humans. EBV is associated with many neoplasms, including Burkitt's lymphoma, Hodgkin's disease, large B-cell lymphoma, leiomyosarcoma, and nasopharyngeal carcinoma. HBV and HCV are associated with hepatocellular carcinoma. HPV is associated with cervical cancer and a variety of anogenital and esophageal neoplasms. Kaposi sarcoma–associated herpesvirus is associated with Kaposi sarcoma and primary effusion lymphoma in persons with HIV infection.

Often, the linkage of a virus to a particular neoplasm can be attributed to transforming properties of the virus itself. For example, EBV encodes several latency-associated proteins that are responsible for immortalization of B cells; these proteins likely play crucial roles in the pathogenesis of EBV-associated malignancies. 220 Similarly, HPV encodes the E6 and E7 proteins that block apoptosis 112 , 113 , 114 and induce cell cycle progression, 110 , 111 respectively. It is hypothesized that unregulated expression of these proteins induced by the aberrant integration of the HPV genome into host DNA is responsible for malignant transformation. 221 The tumorigenicity of polyomaviruses, which are oncogenic in rodent species, is mediated by a family of viral proteins known as tumor (T) antigens. Reminiscent of the HPV E6 and E7 proteins, T antigens induce cell cycling and block the ensuing cellular apoptotic response to unscheduled cell division. 222 The normally episomal polyomavirus genome becomes integrated into cellular DNA during neoplastic transformation of nonpermissive cells unable to support the entire viral replication program, which would otherwise culminate in cell death. Discovery of a human polyomavirus clonally integrated into cells of an aggressive form of skin cancer, Merkel cell carcinoma, 2 substantiates the long-standing suspicion that polyomaviruses can also promote neoplasia in humans.

In other cases, mechanisms of malignancy triggered by viral infection are less clear. HCV is an RNA-containing virus that lacks reverse transcriptase and a means of viral genome integration. However, chronic infection with HCV is strongly associated with hepatocellular cancer. 223 It is possible that increased cell turnover and inflammatory mediators elicited by chronic HCV infection increase the risk of genetic damage, which results in malignant transformation. Some HCV proteins may also play a contributory role in neoplasia. For example, the HCV core protein can protect cells against apoptosis induced by a variety of stimuli, including tumor necrosis factor-α (TNF-α). 224

Viral Virulence Determinants

Viral surface proteins involved in attachment and entry influence the virulence of diverse groups of viruses. For example, polymorphisms in the attachment proteins of influenza virus, 225 , 226 polyomavirus, 227 reovirus, 228 rotavirus, 229 and VEE 230 are strongly linked to virulence and can be accurately termed virulence determinants. Viral attachment proteins can serve this function by altering the affinity of virus–receptor interactions or modulating the kinetics of viral disassembly. Importantly, sequences in viral genomes that do not encode protein can also influence viral virulence. Mutations that contribute to the attenuated virulence of the Sabin strains of poliovirus are located in the 5′ nontranslated region of the viral genome. 231 These mutations attenuate poliovirus virulence by altering the efficiency of viral protein synthesis.

A number of viruses encode proteins that enhance virulence by modulation of host immune responses. Illustrative examples include the influenza A NS1 protein, which interferes with activation of cellular innate immune responses to viral infection, 232 and translation products of the adenovirus E3 transcriptional unit, which serve to prevent cytotoxic T-cell recognition of virally infected cells and block immunologically activated signaling pathways that lead to infected-cell death. 208 , 233 In many cases, these proteins are dispensable for viral replication in cultured cells. In this way, immunomodulatory viral virulence determinants resemble classic bacterial virulence factors such as various types of secreted toxins.

Host Responses to Infection

The immune response to viral infection involves complex interactions among leukocytes, nonhematopoietic cells, signaling proteins, soluble proinflammatory mediators, antigen-presenting molecules, and antibodies. These cells and molecules collaborate in a highly regulated fashion to limit viral replication and dissemination through recognition of broadly conserved molecular signatures, followed by virus-specific adaptive responses that further control infection and establish antigen-selective immunologic memory. The innate antiviral response is a local, transient, antigen-independent perimeter defense strategically focused at the site of virus incursion into an organ or tissue. Mediated by ancient families of membrane-associated and cytosolic molecules known as pattern recognition receptors (PRRs), the innate immune system detects pathogen-associated molecular patterns (PAMPs), which are fundamental structural components of microbial products including nucleic acids, carbohydrates, and lipids. 234 Viral PAMPs in the form of single-stranded (ss)RNA, dsRNA, and DNA evoke the innate immune response through two groups of PRRs: the transmembrane Toll-like receptors (TLRs) and the cytosolic nucleic acid sensors. The latter include retinoic acid inducible gene-I (RIG-I)-like receptors, nucleotide-binding domain and leucine-rich-repeat containing proteins (NLRs) such as NLRP, and DNA sensors. 235 Nucleic acid binding by PRRs activates signaling pathways leading to the production and extracellular release of IFN-α, IFN-β, and proinflammatory cytokines such as interleukin (IL)-1β and IL-18. IFN-α and IFN-β engage the cell surface IFN-α/β receptor and thereby mediate expression of hundreds of gene products that corporately suppress viral replication and establish an intracellular antiviral state in neighboring uninfected cells. Well-described IFN-inducible gene products include the latent enzymes dsRNA-dependent protein kinase (PKR) and 2′,5′-oligoadenylate synthetase (OAS), both of which are activated by dsRNA. 236 PKR inhibits the initiation of protein synthesis through phosphorylation of translation initiation factor eIF2α. The 2′,5′-oligoandenylates generated by OAS bind and activate endoribonuclease RNAse L, which degrades viral mRNA. In addition to mediating an intracellular antiviral state, IFN-α/β also stimulates the antigen-independent destruction of virus-infected cells by a specialized population of lymphocytes known as natural killer (NK) cells. 237 Importantly, IFNs bridge innate and adaptive antiviral immune responses through multiple modes of action, which include enhancing viral antigen presentation by class I MHC proteins, 238 promoting the proliferation of MHC class I–restricted CD8 + CTLs, 239 and facilitating the functional maturation of dendritic cells. 240 Proinflammatory mediators IL-1β and IL-18 pleiotropically stimulate and amplify the innate immune response through induction of other inflammatory mediators, immune cell activation, and migration of inflammatory cells into sites of infection. 241 These molecules perform essential functions in host antiviral defense. 242

The adaptive immune response confers systemic and enduring pathogen-selective immunity through expansion and functional differentiation of viral antigen-specific T and B lymphocytes. Having both regulatory and effector roles, T lymphocytes are centrally positioned in the scheme of adaptive immunity. The primary cell type involved in the resolution of acute viral infection is the CD8 + CTL, which induces lethal proapoptotic signaling in virus-infected cells upon recognition of endogenously produced viral protein fragments presented by cell surface MHC class I molecules. Less frequently, CD4 + T cells, which recognize MHC class II–associated viral oligopeptides processed from exogenously acquired proteins, also demonstrate cytotoxicity against viral antigen-presenting cells. 243 The usual function of CD4 + T lym­phocytes is to orchestrate and balance cell-mediated (CTL) and humoral (B lymphocyte) responses to infection. Classes of CD4 + helper T-cell subsets—Th1, Th2, Th17, Treg (regulatory T), and Tfh (follicular helper T)—have been defined based on characteristic patterns of cytokine secretion and effector activities. 244 , 245 Th1 and Th2 lymphocytes are usually associated with the development of cell-mediated and humoral responses, respectively, to viral infection. Th17 and Treg CD4 + subsets are important for control of immune responses and prevention of autoimmunity, but their precise roles in viral disease and antiviral immunity are not clear. For certain persistent viral infections, such as those caused by HIV and HSV, Treg cells might exacerbate disease through suppression of CTLs or, paradoxically, ameliorate illness by attenuating immune-mediated cell and tissue injury. 246 Tfh cells promote differentiation of antigen-specific memory B lymphocytes and plasma cells within germinal centers. 247 Therefore, Tfh cells likely occupy a central place in the humoral response to viral infection and vaccination. Although Tfh cell functions are not unique to antiviral responses, chronic viral infections including HBV and HIV appear to stimulate proliferation of these cells. 248 , 249 The Tfh phenotype may interconvert with other T-helper lineage profiles and thus represent a differentiation intermediate rather than a unique CD4 + T lymphocyte subset. 245

The primacy of cell-mediated immune responses in combating viral infections is revealed by the extreme vulnerability of individuals to chronic and life-threatening viral diseases when cellular immunity is dysfunctional. Those with acquired immunodeficiency syndrome (AIDS) exemplify the catastrophic consequences of collapsing cell-mediated immunity; progressive multifocal leukoencephalopathy caused by JC polyomavirus, along with severe mucocutaneous and disseminated CMV, HSV, and VZV infections, are frequent complications of vanishing CD4 + T cells. Similarly, iatrogenic cellular immunodeficiency associated with hematopoietic stem cell and solid-organ transplantation or antineoplastic treatment regimens predisposes to severe, potentially fatal infections with herpesviruses and respiratory viral pathogens such as adenovirus, PIV, and RSV, 250 all of which normally produce self-limited illness in immunocompetent hosts. Prevention and management of serious viral respiratory infections are significant challenges in myelosuppression units because of the communicability of respiratory viruses and paucity of effective drugs to combat these ubiquitous agents. Individuals with significantly impaired cell-mediated immunity are also at increased risk for enhanced viral replication and systemic disease following immunization with live, attenuated viral vaccines (e.g., measles-mumps-rubella [MMR] and VZV vaccines). Hence, live viral vaccines are generally contraindicated for immunocompromised persons (see Chapter 321). TNF-α inhibitor therapy, increasingly employed to manage a variety of rheumatologic and inflammatory diseases, enhances the risk of HBV reactivation with potentially life-threatening consequences. 251 Preventive and interventional HBV treatment strategies are necessary to circumvent complications of uncontrolled viral replication in these patients.

In contrast to cell-mediated immune mechanisms, humoral responses are usually not a determinative factor in the resolution of primary viral infections. (One notable exception is a syndrome of chronic enteroviral meningitis in the setting of agammaglobulinemia. 252 ) However, for most human viral pathogens, the presence of antibody is associated with protection against initial infection in vaccinees or reinfection in hosts with a history of natural infection. 253 Longitudinal studies indicate that levels of protective serum antibodies (induced by natural infection or immunization) to common viruses, including EBV, measles, mumps, and rubella, are remarkably stable, with calculated antibody half-lives ranging from several decades to thousands of years. 254 The protective role of antibodies on secondary exposure is frequently explained as interruption of viremic spread where a hematogenous phase is involved, such as occurs with measles, mumps, and rubella viruses, poliovirus, VZV, and most arboviruses. Nevertheless, most human viruses, excluding insect-transmitted agents, enter their hosts by transgression of a mucosal barrier, frequently undergoing primary replication in mucosal epithelium or adjacent lymphoid tissues. Neutralizing IgA exuded onto mucosal epithelial surfaces may protect against primary infection at this portal of viral entry. A classic example is gut mucosal immunity induced by orally administered Sabin poliovirus vaccine containing live-attenuated virus. Secretory IgA against poliovirus blocks infection at the site of primary replication and consequently interrupts the chain of viral transmission, although fully virulent revertant viruses arise at regular frequency in vaccine recipients, who may develop disease and also transmit revertant strains to nonimmune individuals. 255 Clinical and experimental studies of immunity to HIV have led to the recognition that resident immune responses at exposed mucosal surfaces are likely critical components of host resistance to primary HIV infection, and achievement of potent mucosal immunity has emerged as an important consideration for the design of candidate HIV vaccines. 256 Despite the appearance of serum neutralizing antibodies to HIV several weeks after infection, viral eradication is thwarted by selection of neutralization-resistant variant strains from a mutant pool, which is perpetually replenished because of extreme plasticity within neutralization determinants on the viral envelope glycoproteins. 257 Identification of epitopes bound by broadly neutralizing antiviral antibodies has provided potential new targets for structure-based vaccine design. 258

Protection against viral infection by serum immunoglobulins is often correlated with antibody-mediated neutralization of viral infectivity in cultured cells. Antibodies interrupt the viral life cycle at early steps, which may include cross-linking virion particles into noninfectious aggregates, steric hindrance of receptor engagement, and interference with viral disassembly. 259 It is presumed that virus neutralization in cell culture by human serum is reflective of antibody activity in the intact host, but the mechanistic basis of infection blockade and disease prevention by antibodies in vivo is difficult to define precisely. For example, exclusively in vivo functions of the humoral antiviral response include Fc-mediated virion phagocytosis 260 , 261 and antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC responses require effectors from both the innate and adaptive systems, NK cells and antibodies, respectively. 262 The basis of ADCC is FcγRIIIa receptor-dependent recognition by NK cells of virus-specific IgG bound to antigens expressed on the surface of infected cells, leading to release of perforin and granzymes from NK cells that eventuate in target cell apoptosis. Neutrophils, lymphocytes, and macrophages also possess Fc receptors and may participate in ADCC.

Key References

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