The Journal of Infectious Diseases

PERSPECTIVE

The Extended Impact of Human Immunodeficiency Virus/

AIDS Research
Tara A. Schwetz, and Anthony S. Fauci
Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Abstract
Human immunodeficiency virus (HIV) is one of the most extensively studied viruses in history, and numerous extraordinary sci-
entific advances, including an in-depth understanding of viral biology, pathogenesis, and life-saving antiretroviral therapies, have

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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.

Keywords.  HIV/AIDS; collateral advantages.

The first cases of AIDS were reported in the the most impressive advances in HIV/ being made in the quest for a safe and
United States 37 years ago. Since then, >77 AIDS research have come in the arena of effective HIV vaccine [5].
million people have been infected world- antiretroviral therapy. Before the develop- The enormous investment in HIV
wide, resulting in over 35 million deaths. ment of these life-saving drugs, AIDS was research is clearly justified and validated
Currently, there are 36.9 million people an almost universally fatal disease. Since purely on the basis of advances specifi-
living with human immunodeficiency the demonstration in 1987 that a single cally related to HIV/AIDS. However, the
virus (HIV), 1.8 million new infections, drug, zidovudine, better known as azi- collateral advantages of this investment
and nearly 1 million AIDS-related deaths dothymidine or AZT, could partially and above and beyond HIV/AIDS have been
annually [1]. Billions of research dollars temporarily suppress virus replication [2], profound, leading to insights and con-
have been invested toward understanding, the lives of people living with HIV have crete advances in separate, diverse, and
treating, and preventing HIV infection. been transformed by the current avail- unrelated fields of biomedical research
The largest funder of HIV/AIDS research ability of >30 antiretroviral drugs that, and medicine. In the current Perspective,
is the National Institutes of Health (NIH), when administered in combinations of we discuss a few select examples of the
investing nearly $69 billion in AIDS 3 drugs, now in a single daily pill, sup- positive spin-offs of HIV/AIDS research
research from fiscal years 1982–2018. press the virus to undetectable levels. on other scientific areas (Table 1).
Despite the staggering disease burden, the Today, if a person in their 20s is infected
scientific advances directly resulting from and given a combination of antiretroviral Regulation of the Human Immune System
investments in AIDS research have been drugs that almost invariably will durably Congenital immunodeficiencies have
extraordinary. HIV is one of the most suppress virus to below detectable levels, been described as “experiments of nature,”
intensively studied viruses in history, they can anticipate living an additional whereby a specific defect in a single com-
leading to an in-depth understanding of 50 years, allowing them almost a normal ponent of the complex immune system
viral biology and pathogenesis. However, life expectancy [3]. In addition, a person sheds light on the entire system. Such is
receiving antiretroviral therapy with an the case with AIDS, an acquired defect in
Received 25 June 2018; editorial decision 10 July 2018; undetectable viral load will not transmit the immune system whereby HIV specif-
accepted 17 July 2018; published online August 28, 2018
Correspondence: A.  S. Fauci, MD, Office of the Director,
virus to their uninfected sexual partner. ically and selectively infects and destroys
National Institute of Allergy and Infectious Diseases, National This strategy is referred to as “treatment the CD4+ subset of T lymphocytes [6]. In
Institutes of Health, 9000 Rockville Pike, Bldg 31, Suite 7A03,
as prevention” [4]. Also, administration this respect, HIV infection functions as
Bethesda, MD 20892 ([email protected]).
The Journal of Infectious Diseases®  2019;219:6–9 of a single pill containing 2 antiretroviral a natural experiment that elucidates the
Published by Oxford University Press for the Infectious Diseases drugs taken daily by an at-risk uninfected complexity of the human immune system.
Society of America 2018. This work is written by (a) US
Government employee(s) and is in the public domain in the US.
person decreases the chance of acquiring The selectivity of this defect and its result-
DOI: 10.1093/infdis/jiy441 HIV by >95%. Finally, major strides are ing catastrophic effect on host defense

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Table 1.  Positive Spin-offs of Human Immuno­ Probing the B-Cell Repertoire the loss of CD4+ T lymphocytes [16].
deficiency Virus/AIDS Research on Other Areas The past decade has witnessed extraor- While much of the initial research on
of Medicine
dinary advances in probing the human CD4+ T lymphocytes was possible due
Regulation of the human immune system B-cell lineage resulting from the avail- to existing flow cytometry technologies,
Targeted antiviral drug development ability of highly sophisticated technol- probing the complexities of immune
Probing the B-cell repertoire ogies in cellular cloning and genomic dysregulation in HIV infection spurred
Structure-based vaccine design sequencing [9]. AIDS research aimed at the development of multicolor cytofluo-
Advances in HIV/AIDS-related technologies
developing broadly reactive neutraliz- rometric technologies that have proven
Role of immune activation in disease
pathogenesis ing antibodies against HIV and an HIV extremely useful for studying a variety of
Comorbidities in HIV disease vaccine that could induce broadly neu- other diseases characterized by immune
Abbreviation: HIV, human immunodeficiency virus.
tralizing antibodies has greatly advanced dysfunction [17]. The reality of utiliz-
the field of interrogation of human B-cell ing these technologies in resource-poor
lineages, leading to greater insights into areas accelerated the advancement of

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the humoral response to other infectious new simplified, automated, affordable,
mechanisms, as manifested by the wide diseases, including Ebola [10], Zika [11], and portable point-of-care devices with
range of opportunistic infections and neo- and influenza [12], as well as a range of broader implications for clinical medi-
plasms, underscore the critical role this cell autoimmune, neoplastic, and other non- cine [18].
type plays in the overall regulation of the communicable diseases [13].
human immune system. This has provided Role of Immune Activation in Disease Pathogenesis
substantial insights into the pathogenesis Structure-Based Vaccine Design Studying the pathogenesis of HIV disease
of an array of other diseases character- Although a safe and effective HIV vaccine has clearly demonstrated that aberrant
ized by aberrancies of immune regulation. has not yet been developed, the discipline immune activation stimulated by virus
Additionally, the in-depth study of immune of structure-based vaccine design using replication is the driving force of HIV
dysfunction in HIV disease has shed light protein X-ray crystallography and cryo- replication [19]. In essence, the somewhat
on the role of the immune system in sur- electron microscopy has matured greatly paradoxical situation exists whereby the
veillance against a variety of neoplastic in the context of HIV vaccine research. very immune activation triggered by the
diseases, such as non-Hodgkin lymphoma The design of immunogens based on the virus in an attempt to control virus rep-
and Kaposi sarcoma. As a result of its asso- precise conformation of epitopes in the lication creates the microenvironment
ciation with HIV/AIDS, Kaposi sarcoma viral envelope as they bind to neutraliz- where the virus efficiently replicates. Even
was discovered to be caused by human ing antibodies has been perfected within when the virus is effectively suppressed
herpesvirus 8 [7]. the arena of HIV vaccine immunogen by antiretroviral drugs, a low degree of
design. This has had immediate positive immune activation persists [20]. In this
Targeted Antiviral Drug Development spinoffs in the design of vaccines for regard, the flagrant immune activation
Targeted antiviral drug development did other viruses, such as respiratory syncy- associated with uncontrolled virus repli-
not begin with HIV infection. However, tial virus, in which the prefusion glyco- cation, as well as the subtle immune acti-
the enormous investments in biomed- protein was identified as the important vation associated with control of virus
ical research supported by the NIH immunogen for a vaccine using struc- replication, are important pathogenic
and in drug development supported by ture-based approaches [14]. triggers of the increased cardiovascular
pharmaceutical companies led to highly and other organ system diseases associ-
effective antiretroviral drugs targeting Advances in HIV/AIDS-Related Technologies ated with HIV infection. This direct asso-
the enzymes reverse transcriptase, pro- Insights into the basic immunology of ciation of even subtle levels of immune
tease, and integrase, among other vul- HIV drove the development and opti- activation seen in HIV infection with a
nerable points in the HIV replication mization of several broadly applicable variety of systemic diseases has led to con-
cycle, and have transformed the field of technologies. Using inactivated HIV as siderable insight into the role of immune
targeted drug development, bringing it to a means of altering T lymphocytes to activation and inflammation in human
an unprecedented level of sophistication. modulate the immune response, safe disease [21]. For example, recognition of
Building on 3 decades of experience, this lentiviral gene therapy vectors are now the increased incidence of heart disease
HIV model has been applied in the suc- US Food and Drug Administration– in the HIV population that is associated
cessful development of antiviral drugs for approved to treat certain cancers (eg, with chronic inflammation has stimulated
other viral diseases, including the highly acute lymphoblastic leukemia) [15]. interdisciplinary advances in understand-
effective and curative direct-acting anti- Additionally, it was discovered early in ing and treating coronary heart disease
virals for hepatitis C [8]. the epidemic that HIV is associated with apart from HIV infection [22].

PERSPECTIVE • JID 2019:219 (1 January) • 7
Comorbidities in HIV Disease Potential conflicts of interest. Both virus infection therapy. J Infect Dis
Antiretroviral therapy, which has trans- authors: No reported conflicts of inter- 2013; 207(Suppl 1):S33–9.
formed HIV treatment, is shifting the est. Both authors have submitted the 9. Boyd SD, Crowe JE Jr. Deep sequenc-
incidence of certain diseases in people ICMJE Form for Disclosure of Potential ing and human antibody repertoire
living with HIV. Even when well-con- Conflicts of Interest. Conflicts that the analysis. Curr Opin Immunol 2016;
trolled by antiretrovirals, HIV disease is editors consider relevant to the content of 40:103–9.
associated with an increased incidence of the manuscript have been disclosed. 10. Flyak AI, Kuzmina N, Murin CD,

diseases, such as cardiovascular disease, et  al. Broadly neutralizing antibod-
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