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Aging on antiretrovirals: reviewing the need for pharmacologic data in elderly people with HIV

AIDS. 38(11):1609-1616, September 01, 2024.

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Characterization of the gut butyrate-producing bacteria and lipid metabolism in African green monkey as a natural host of simian immunodeficiency virus infection

AIDS. 38(11):1617-1626, September 01, 2024.

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A predictive model for HIV-related lymphoma

AIDS. 38(11):1627-1637, September 01, 2024.

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Point-of-care urine tenofovir test predicts future HIV preexposure prophylaxis discontinuation among young users

AIDS. 38(11):1671-1676, September 01, 2024.

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The impact of financial incentives on mental health among adults in HIV care in Lake Zone, Tanzania

AIDS. 38(11):1677-1685, September 01, 2024.

Longitudinal viral load outcomes of adults with HIV after detectable viremia on tenofovir, lamivudine, and dolutegravir

AIDS. 38(11):1714-1719, September 01, 2024.

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Rosuvastatin was not beneficial in reducing arterial stiffness and may be associated with cardiometabolic adverse events in men with HIV

AIDS. 38(11):1720-1721, September 01, 2024.

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Impact of rosuvastatin on pulse-wave velocity in men with HIV at moderate cardiovascular risk

AIDS. 38(11):1722-1724, September 01, 2024.

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Concomitant use of anabolic androgen steroids and cabotegravir/rilpivirine leading to virological failure and development of two-class resistance

AIDS. 38(11):1728-1729, September 01, 2024.

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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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Volume 27, Number 6—June 2021

Perspective

Reflections on 40 years of aids.

Cite This Article

June 2021 marks the 40th anniversary of the first description of AIDS. On the 30th anniversary, we defined priorities as improving use of existing interventions, clarifying optimal use of HIV testing and antiretroviral therapy for prevention and treatment, continuing research, and ensuring sustainability of the response. Despite scientific and programmatic progress, the end of AIDS is not in sight. Other major epidemics over the past decade have included Ebola, arbovirus infections, and coronavirus disease (COVID-19). A benchmark against which to compare other global interventions is the HIV/AIDS response in terms of funding, coordination, and solidarity. Lessons from Ebola and HIV/AIDS are pertinent to the COVID-19 response. The fifth decade of AIDS will have to position HIV/AIDS in the context of enhanced preparedness and capacity to respond to other potential pandemics and transnational health threats.

“When the history of AIDS and the global response is written, our most precious contribution may well be that, at a time of plague, we did not flee, we did not hide, we did not separate ourselves.”

—Jonathan Mann, Founding Director of Project SIDA and the World Health Organization Global Programme on AIDS, 1998

Forty years ago, on June 5, 1981, the Centers for Disease Control’s Morbidity and Mortality Weekly Report described 5 cases of Pneumocystis pneumonia in gay men ( 1 ). That report heralded the HIV/AIDS pandemic, which has resulted in over 75 million HIV infections and 32 million deaths. In 2011, we reviewed 30 years of AIDS and commented that the HIV/AIDS response would be a benchmark against which responses to other health threats would be compared ( 2 ). After 40 years of AIDS, we present our personal reflections on scientific and global health evolution over the fourth decade of AIDS in a world that has recently suffered other major epidemics. We focus on biomedical advances because these have had the greatest effect on HIV transmission and disease; advances in structural and behavioral interventions are reviewed in the CDC Compendium of Evidence-Based Interventions and Best Practices for HIV Prevention ( 3 ).

After the initial MMWR report was published, it took 2–3 years for the cause of AIDS, the novel retrovirus designated HIV, to be identified ( 4 , 5 ), and many more years to uncover its simian origin ( 6 ). Because of the asymptomatic spread of HIV, the long incubation period before disease, and transmission through sex and blood, millions of persons around the world, including several hundred thousand in the United States, were infected by the time the first AIDS cases were reported. The epidemiology and natural history of HIV infection, combining elements of acute and chronic diseases, ensured a diverse and long-lasting pandemic.

The history of HIV/AIDS and the struggle to contain it have seen the best and worst of human nature. Frequent examples of discrimination and exclusion are contrasted by leadership, illustrated by community activists ( 7 ), Jonathan Mann molding the first global response ( 8 ), Kofi Annan rallying the United Nations behind the search for a global fund ( 9 ), and President George W. Bush committing United States generosity to a war on HIV/AIDS of uncertain duration ( 10 ). Despite continued instances of injustice, the story has overall been a positive one, providing lessons for how to respond to other epidemic and pandemic threats.

Evolving Epidemiology

The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that in 2019, 38 million persons worldwide were living with HIV, 1.7 million became newly infected, and 690,000 died with HIV disease ( 11 ). Compared with 2010 estimates, overall HIV incidence in 2019 decreased by 23% and mortality by 37%. However, age stratification shows that new infections have decreased by 52% among children but by only 13% among adults. With reduced mortality rates yet continued HIV incidence and population growth, the overall number of persons living with HIV was 24% greater in 2019 than in 2010.

Global summaries hide regional differences. The epicenter of the pandemic remains in East and southern Africa, which account for 54% of all HIV-infected persons and 43% of incident HIV infections and deaths ( 11 ). High prevalence of HIV-infected persons with unsuppressed viremia predicts high incidence and maintenance of community infection, an observation that applies to regions and countries, as well as specific populations such as men who have sex with men (MSM).

The next greatest HIV burden is in the Asia and Pacific region, where the population is vastly greater than that of East and southern Africa but there are 3.5 times fewer HIV-infected persons ( 11 ). Despite overall prevention progress, HIV incidence has not declined equally everywhere; little success has been seen in eastern Europe, the Middle East, and Central Asia.

Ever clearer is the global burden of HIV in key populations: MSM, transgender persons, people who inject drugs, sex workers and their clients, and incarcerated persons. In 2019, an estimated 62% of all new HIV infections were in members of those key populations ( 11 ). In 7 of the 8 UNAIDS regions, key populations accounted for 60%–99% of incident HIV infections; only in East and southern Africa, where the proportion was 28%, were new infections predominant in general populations ( 11 ).

Among high-income nations, the most heavily affected country is still the United States. In 2018, a total of 37,881 HIV infections were newly reported, with regional differences ( 12 ). In the South, the rate of new infections was more than twice that for the Midwest, where the rate was the lowest. Major disparities by race/ethnicity persist; the rate among Black/African American persons is 2 times that among Hispanic and 8 times that among White persons. Also associated with higher rates are factors indicating social deprivation and poverty, even allowing for racial and ethnic disparities. Among new HIV infections, 70% resulted from male-to-male sex. A cause for concern is potential overlap between the HIV/AIDS and opioid epidemics through increased drug injection and needle sharing, which has resulted in explosive HIV outbreaks ( 13 ).

Evolving Science and Program

In our 2011 commentary ( 2 ), we considered the following as priorities: improving use of existing interventions, defining how best to use HIV testing and antiretroviral therapy (ART) for prevention as well as treatment, continuing the quest for new knowledge and interventions, and ensuring sustainability of the global response. By and large, progress has been made on all fronts.

After the CAPRISA 004 trial of precoital and postcoital use of tenofovir gel was published in 2010 ( 14 ), the Ring ( 15 ) and Aspire ( 16 ) studies (randomized, placebo-controlled trials in South Africa) examined the protective efficacy of a self-inserted vaginal ring impregnated with slow-release dapivirine, a nonnucleoside reverse transcription inhibitor. The overall efficacy rates for reducing HIV incidence were 31% (Ring) and 27% (Aspire); many questions about overall efficacy, adherence, and differences by age remained. This collective experience provided proof of concept for woman-controlled prevention but did not provide the definitive public health solution to high HIV incidence among young women in Africa.

Four pivotal randomized trials ( 17 – 20 ) of oral preexposure prophylaxis (PrEP) with Truvada (combination of tenofovir and emtricitabine) were pivotal for international licensing of the compound. The relevant trials studied MSM, transgender women having sex with men, and at-risk heterosexual persons. A review of evidence considered another 9 studies, some of tenofovir alone, in different populations including people who inject drugs ( 21 ). The pivotal trials showed reduced HIV incidence (44%–86%) with Truvada use. However, a consistent observation has been a strong association between efficacy and adherence; PrEP is effective, but the drugs need to be taken.

Subsequent research focused on differential tissue penetration of drugs to relevant anatomic sites in men and women and on modes of drug delivery. HIV Prevention Trials Network (HPTN) studies compared the prevention efficacy of the long-acting injectable drug cabotegravir with Truvada in men and transgender women who have sex with men (study 083 [ 22 ]) and in heterosexual women (study 084 [ 23 ]). Interim results showed that cabotegravir, delivered every 8 weeks by injection, was associated with 66% lower incidence than oral Truvada in study 083 and 89% less in study 084. The long half-life of cabotegravir enables intermittent dosing, but waning drug levels over time may become subtherapeutic, thus requiring additional interventions to prevent infection and preclude development of drug resistance.

In its 2016 guidelines, the World Health Organization (WHO) recommended public health use of PrEP, as have other national and international regulatory or advisory bodies. However, the enthusiasm engendered by PreP science needs to be tempered by consideration of cost, need for rigorous adherence, rising rates of other sexually transmitted infections and thus need for continued condom use, and contraception for women. Long-acting injectables could be a major advance, but accessibility and logistics for their delivery need to be considered.

Mathematical modeling and ecologic studies suggested that greatly increased delivery of ART could reduce HIV transmission at the community level. The definitive study showing that ART provided prevention benefits was the landmark HPTN 052 study ( 24 ), published in interim form in 2011. This trial among discordant couples found a 96% reduction in HIV transmission among those who started ART early versus those for whom it was deferred. Combined with an influential modeling study ( 25 ) that suggested that regular HIV testing and immediate use of ART could suppress and perhaps ultimately eliminate HIV transmission, the results of HPTN 052 led to studies in East and southern Africa of the so-called test and treat intervention ( 26 – 29 ). These studies were community randomized evaluations of widespread HIV testing and immediate ART compared with standard care; the primary endpoint was HIV incidence. These large, expensive implementation science studies yielded rich information but did not lead to local HIV elimination. Of the 4 studies, 2 showed no significant incidence reduction and the other 2 showed 20%–30% reduction.

One of the reasons for the unexpectedly modest differences in HIV incidence between intervention and control communities in the test and treat study was changing global practice with regard to when to start ART. In 2015, results of the START ( 30 ) and TEMPRANO ( 31 ) trials showed unequivocally that immediate ART, irrespective of CD4+ lymphocyte count, resulted in reduced HIV-associated disease and death, ending more than 2 decades of argument about when to start treatment. WHO rapidly changed global recommendations to immediately start ART, one result of which was erosion of differences between intervention and control communities in the test and treat trials.

Although test and treat did not reduce HIV incidence to the extent hoped for, the accumulated evidence supports the notion of early, universal ART for extending the lives of HIV-positive persons as well as reducing the prevalence of unsuppressed viremia, the driver of HIV transmission. Large observational studies ( 32 ) showed that persons with suppressed viremia do not transmit the virus sexually, leading to the slogan “U = U”—undetectable equals untransmittable. This experience provides a much more compelling argument for active HIV case finding through increased HIV testing and partner notification, to enhance individual and public health through early treatment.

Although none of the approaches described provides a unique solution, the combination of widespread HIV testing, early ART for those infected, and PrEP for those at risk offers opportunity for substantially limiting the epidemic. Such approaches have been associated with reductions in new HIV infections among MSM in London, UK ( 33 ), and in New South Wales, Australia ( 34 ). In the United States, these advances—testing, case finding including through partner notification, universal treatment, PrEP, and rapid molecular investigation of clusters for service provision—have been incorporated into a revised national strategy for HIV elimination ( 35 ).

Progress toward an HIV vaccine remains discouraging. The only report of protective efficacy, published in 2009, has been the RV-144 study in Thailand ( 36 ), which investigated use of a recombinant canarypox vector vaccine (ALVAC-HIV) delivered in 4 monthly priming injections followed by a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E) given in 2 additional injections. Reported efficacy was 26%–31%, but statistical and technical interpretation of these results was controversial ( 37 ). In 2016, the HVTN 702 study was launched in South Africa and used the same product as in the Thailand trial but modified for the dominant subtype C. After interim analysis, the study was halted for futility in early 2020 ( 38 ). Other efficacy studies of vaccines based on so-called mosaic immunogens from diverse HIV subtypes are in progress.

There has been great interest in broadly neutralizing antibodies to HIV, which some infected persons produce naturally and which might protect against a wide variety of strains. Two international trials of infusions with a broadly neutralizing antibody, VRC01, every 8 weeks showed relative protection against sensitive strains but no significantly reduced HIV incidence overall ( 39 ).

In 2014, UNAIDS launched its 90:90:90 initiative, aiming for 90% of persons with HIV infection to be diagnosed, 90% of those with an HIV diagnosis to receive ART, and 90% of those receiving treatment to show viral suppression by 2020. Globally, the respective proportions in 2019 were 81%, 82%, and 88%, so that an estimated 59% of persons living with HIV were showing viral suppression. Initially, 90:90:90 (with a goal of these numbers being 95s by 2030) was an advocacy proposal rather than an evidence-based initiative, but these targets have become adopted as policy promising “epidemic control,” itself a concept requiring precise definition ( 40 ).

ART scale-up, increased male circumcision, and prevention of mother-to-child transmission have all contributed to encouraging advances in the most heavily affected regions of Africa ( 11 , 41 , 42 ). Successful program implementation and declines in new HIV infections and deaths, combined with scientific progress, have led to a certain complacency that “AIDS is over.” Former US Secretary of State Hillary Clinton and staff promoted the idea that current tools could abruptly halt the epidemic. We largely agree with the 2018 judgment of the International AIDS Society–Lancet Commission on AIDS: “The HIV/AIDS community made a serious error by pursuing ‘the end of AIDS’ message” ( 43 ). Key populations, hiding in obscurity as well as in plain sight, will probably remain as reservoirs, even with highly performing programs. Experience in East and southern Africa has highlighted the challenge of adequate service provision to youth and men. Stigma and discrimination remain barriers in many parts of the world, and lack of an HIV cure (a priority research area) and vaccine remain scientific obstacles ( 44 ).

Evolving Global Health

The HIV/AIDS pandemic has evolved in parallel with other global health events that necessarily influence how HIV/AIDS is perceived and prioritized. In a 2012 paper, author K.D.C. suggested that global health trends could best be analyzed through the lenses of development, public health, and health security ( 45 ). The fourth decade of AIDS started in the aftermath of the global financial crisis and the influenza (H1N1) pandemic and is finishing amid the coronavirus disease (COVID-19) pandemic. Although substantial progress has been made toward reducing maternal deaths, improving child survival rates, and scaling up programs for HIV/AIDS, malaria, and tuberculosis, the past decade has seen major disease outbreaks and a consequent focus on health security. Because of its sociodemographic effects, AIDS was portrayed as a security issue in United Nations discussions early in this century. With massive scale-up of treatment and prevention, HIV/AIDS is now perceived as another public health priority rather than a security emergency.

In 2014, Ebola was reported in Guinea, Liberia, and Sierra Leone, far west of previously recognized outbreaks. The epidemic lasted until mid-2016 and ultimately resulted in 28,646 reported cases and 11,323 deaths ( 46 ). Infections were exported to 3 other countries in Africa, several countries in Europe, and the United States. This health crisis resulted in widespread fear of possible global spread, unparalleled global mobilization of emergency health assistance including use of armed forces of the different high-income countries, and political involvement at the highest levels of governments and the United Nations. Subsequent outbreaks of Ebola have occurred in Uganda and the Democratic Republic of the Congo (DRC), including a large epidemic in conflict-ridden eastern DRC in 2018–2020 that resulted in 3,481 reported cases and 2,299 deaths ( 47 ). Underemphasized aspects of these Ebola epidemics were that cases over the past 6 years represent more than 90% of all cases reported cumulatively since recognition of Ebola in 1976; that vast geographic distances were involved; and that these outbreaks were largely urban, sometimes involving capital and other major cities. Ebola epidemiology has changed from that of an exotic, remote infection in Africa to one capable of causing extensive urban outbreaks threatening global health ( 48 ). Also of note was that field research conducted during the outbreaks under the most difficult conditions showed efficacy of a vaccine and therapeutics, both now considered the standard of care for Ebola ( 49 , 50 ).

Over the past decade, arboviral epidemic activity has been diverse. The epidemics of yellow fever in Angola and the DRC in 2015–2016 were the world’s largest over the past 30 years. A total of 965 cases and 400 deaths were reported, but true numbers were far greater. Over 30 million persons were vaccinated, and shortage of yellow fever vaccine required healthcare providers to resort to the untested practice of fractionating vaccine doses ( 51 ). Huge epidemics of chikungunya and dengue occurred internationally; virus was transmitted to areas previously considered at low risk, such as Europe ( 52 ). In 2015, the Zika epidemic raised global concern when infection with this virus was shown to be associated with microcephaly in infants and with Guillain-Barré syndrome and to be sexually transmissible. The outbreak resulted in at least 3,700 cases of birth defects in the Americas ( 53 ).

In 2005, after the outbreak of severe acute respiratory syndrome (SARS), WHO revised its International Health Regulations ( 54 ). A key change was authority to declare a Public Health Emergency of International Concern, a health emergency that could result in international spread or required coordinated action. WHO has implemented this authority only 6 times, 5 of them during the fourth decade of AIDS: for polio (2014), Ebola (2014 and 2019), Zika (2015), and COVID-19 (2019).

Related to health security are the interrelated challenges of global warming, demographic change, and migration. Climate change affects social and environmental determinants of health, such as access to clean air, water, shelter, and arable lands, but also exerts direct health effects. The United Nations High Commissioner for Refugees characterized 2010–2019 as “a decade of displacement,” during which 100 million persons were forced to flee their homes, many because of conflict such as that in the Middle East. During 2014–2020, some 20,000 migrants crossing the Mediterranean Sea to Europe drowned, and another 12,000 or more were unaccounted for.

Broad themes that have dominated global health discourse include the transition from the era of the Millennium Development Goals (MDGs; 2000–2015) to that of the broader Sustainable Development Goals (SDGs; 2015–2030) ( 55 ) and the issue of universal health coverage. Other disease-specific programs require continued support, such as the unfinished efforts to eradicate polio and Guinea worm disease. The MDGs had 3 specific health goals relating to child survival; maternal health; and HIV/AIDS, tuberculosis, and malaria. Only 1 of the 17 SDGs is devoted to health, SDG3, which has 13 targets and 28 indicators. Specifically, SDG3 calls for: “By 2030, end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases.” Another target and WHO priority is provision of universal health coverage, global access to decent healthcare, and protection against penury from out-of-pocket health expenditures. HIV/AIDS exists in a crowded and complex global health space.

Preparing for the Fifth Decade of AIDS

As the world emerged from the financial crisis a decade ago, there was concern that HIV/AIDS funding might be constrained. Development assistance for health reached $40.6 billion in 2019, an increase of 15% over the amount in 2010 ( 56 ). Approximately half of this assistance goes to HIV/AIDS, especially for treatment, and to newborn, maternal, and child health. Thus, although health security has eclipsed health development and global public health in this fourth decade of AIDS, financial commitments have been largely maintained.

The overall annual spending on HIV/AIDS by low- and middle-income countries is ≈$20.2 billion, of which ≈$9.5 billion represents donor funding. UNAIDS consistently communicates that to meet SDG targets, overall spending on HIV/AIDS needs to increase by ≈40%. Nonetheless, this HIV-specific spending is privileged compared with funding for other high-impact diseases in low-income settings, such as malaria and tuberculosis. AIDS is no longer among the 10 leading causes of death globally and is now widely viewed as a medically manageable disease. HIV/AIDS prioritization and funding may be justified by the youthful groups affected and its lifelong nature, but this view may be increasingly challenged. Expecting the United States to pay indefinitely for most of the world’s HIV/AIDS response is unrealistic. The end of the SDG era in 2030 will probably come with reappraisal of global commitments, including those for global health funding, disease-specific focus, and maintenance of single-disease organizations such as UNAIDS. Over the coming years, HIV/AIDS programs need to show good fiscal management and epidemiologic results, and affected countries need to shoulder an increased share of their disease burdens.

Lessons from HIV/AIDS and Other Epidemics

The most dramatic epidemics in recent time (COVID-19 [ 57 ], Ebola, and HIV/AIDS) involve quite different biological agents and challenges yet also raise common themes and questions. Especially needed are global responses to challenges that transcend national borders. Pathogen emergence is enhanced by globalization, but globalized systems are needed to address an interconnected worldwide emergency. The slogan “no one is safe until everyone is safe” has been heard in relation to COVID-19, but it was said years ago about HIV. And global health needs global funding.

Individual leaders and organizations have performed valiant work on COVID-19, yet countries have isolated themselves in all senses, resulting in global fragmentation. Major powers look inward yet are reluctant to cede space, and the influence of multilateral agencies is limited. WHO was heavily criticized after the Ebola epidemic in West Africa but is constrained by restricted authority, inadequate funding, and unrealistic expectations from member states. Repeated calls for WHO reform are unclear about what is really wanted.

Honesty is required concerning preparedness and surveillance. The Ebola epidemic in West Africa became as severe as it did because the 3 affected countries had been neglected for years and had no functioning surveillance and public health infrastructure. We cannot say that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was completely unexpected; the literature on pandemic threats is voluminous. SARS in 2002–2003 was severe but not widespread; the 2009 influenza (H1N1) pandemic was widespread but not severe. It is hubristic to assume that pathogen severity and spread would always segregate, yet we were not prepared. Preparedness metrics can give false reassurance, witnessed by the lamentable response to COVID-19 in the United States in 2020. “Never again” was the mood after the Ebola epidemic in West Africa, but preparedness just seems too hard and costly. Perhaps true preparedness exists only in the military, where personnel train continuously for wars they hope will never happen.

As a result of technologic advances such as whole-genome sequencing, scientific progress on COVID-19 has been breathtakingly rapid compared with early laboratory research on HIV. We hope to not see a replay of the early history of ART, with scientific advances relating to COVID-19, and specifically vaccines, not being rapidly or equitably accessible everywhere. “Vaccine nationalism” is a new term raising the specter of lower risk groups in high-income countries receiving vaccine before, for example, frontline healthcare workers in low-income settings. Healthcare workers have been disproportionately affected by Ebola and COVID-19, highlighting the need for much greater investment in infection prevention and control in healthcare settings worldwide. Attention and innovation are required to ensure maintenance of HIV and other essential public health services amid other outbreaks such as COVID-19.

Although initially slow, the HIV/AIDS response over the years has been a beacon in global health for respect for individuals and their rights and for health equity. More reflection is required with regard to what the responses to HIV and Ebola have taught us and how they might be relevant to COVID-19 and other future epidemics.

Conclusions

Although great need remains, the past decade has seen scientific and programmatic successes with regard to the HIV/AIDS priorities we defined after 30 years of AIDS. Existing interventions have been scaled up, and new tools such as PrEP and long-lasting drug preparations have been introduced. The roles of HIV testing and ART for treatment and prevention have been clarified, and the need for immediate ART for all HIV-infected persons has been proven. The global HIV/AIDS response has been sustained, financing has been maintained, and the world has kept focus on the SDGs. Mann’s judgment that “we did not separate ourselves” remains justified. We must also accept that political promises of “the end of AIDS” were hyperbole that current epidemiology does not support.

The COVID-19 pandemic has exploited the fault lines of global systems and existing inequalities in a way that HIV did early on. Regrettably, the solidarity that HIV/AIDS engendered has not yet been carried over. In retrospect, the recent epidemics of Ebola in West Africa and DRC were preparation for the COVID-19 pandemic, but follow-through was lacking. The fifth decade of AIDS will take us to the SDG target date and reassessment of global health and development priorities. HIV/AIDS may not be central to global health discourse as it was earlier, but it will remain a yardstick by which to judge commitment and efforts, including, and especially in relation to, health security.

On February 7, 2021, the Ministry of Health of DRC reported a laboratory-confirmed case of Ebola in North Kivu Province, the most heavily affected province during the 2018–2020 outbreak in eastern Congo. The case-patient experienced symptom onset on January 25, 2021, and died in Butembo, a city of ≈1 million persons, on February 4, 2021. She was reportedly linked epidemiologically to an Ebola survivor, and genetic sequencing reportedly showed phylogenetic association with the earlier outbreak rather than a new spillover event. As of February 8, 2021, a total of 118 contacts were being investigated ( https://www.who.int/emergencies/diseases/ebola/ebola-2021-north-kivu , https://www.who.int/csr/don/10-february-2021-ebola-drc/en ).

Separately, on February 14, 2021, the Ministry of Health of the Republic of Guinea reported an outbreak of Ebola in the subprefecture of Gouécké, Nzérékoré Region, the first report of Ebola in Guinea since the 2014–2016 epidemic. The index case-patient, a nurse, experienced symptoms on January 18, 2021, and died on January 28, 2021. A total of 6 secondary Ebola cases were reported, 1 in a traditional practitioner who cared for the index case-patient and 5 in family members attending her subsequent funeral. Of the 7 case-patients, 5 died. As of February 15, 2021, a total of 192 contacts were being investigated, including in the capital city, Conakry ( https://www.who.int/emergencies/diseases/ebola/ebola-2021-nzerekore-guinea , https://www.who.int/csr/don/17-february-2021-ebola-gin/en ).

Dr. De Cock retired from CDC in December 2020. He had previously served as founding director of Projet RETRO-CI, Abidjan, Côte d’Ivoire; director of the CDC Division of HIV/AIDS Prevention, Surveillance and Epidemiology; director of the WHO Department of HIV/AIDS; founding director of the CDC Center for Global Health; and director, CDC Kenya.

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DOI: 10.3201/eid2706.210284

Original Publication Date: April 29, 2021

Table of Contents – Volume 27, Number 6—June 2021

Please use the form below to submit correspondence to the authors or contact them at the following address:

Kevin M. De Cock, c/o Miriam McNally, 669 Palmetto Ave, Suites H–I, Chico, CA 95926, USA, and PO Box 25705-00603, Lavington, Nairobi, Kenya

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AIDS Research and Therapy

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The emergence and evolution of the research fronts in HIV/AIDS research

David fajardo-ortiz.

1 Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico

Malaquias Lopez-Cervantes

Michel dumontier.

2 Institute of Data Science, Maastricht University, Maastricht, The Netherlands

Miguel Lara

3 Instituto de Biología, Universidad Nacional Autónoma de México, Mexico City, Mexico

Hector Ochoa

4 Colegio de la Frontera Sur, Chiapas, Mexico

Victor M. Castano

5 Centro de Física Aplicada y Tecnología Avanzada, Universidad Nacional Autónoma de México, Queretaro, Mexico

• Conceptualization: DF-O VMC.
• Data curation: DF-O.
• Formal analysis: DF-O.
• Investigation: DF-O.
• Methodology: DF-O.
• Project administration: DF-O.
• Resources: DF-O.
• Supervision: DF-O VMC.
• Validation: DF-O.
• Visualization: DF-O.
• Writing – original draft: DF-O VMC ML-C LD MD ML HO.
• Writing – review & editing: DF-O MD.

Associated Data

All relevant data are within the paper and its Supporting Information files.

In this paper, we have identified and analyzed the emergence, structure and dynamics of the paradigmatic research fronts that established the fundamentals of the biomedical knowledge on HIV/AIDS. A search of papers with the identifiers "HIV/AIDS", "Human Immunodeficiency Virus", “HIV-1” and "Acquired Immunodeficiency Syndrome" in the Web of Science (Thomson Reuters), was carried out. A citation network of those papers was constructed. Then, a sub-network of the papers with the highest number of inter-citations (with a minimal in-degree of 28) was selected to perform a combination of network clustering and text mining to identify the paradigmatic research fronts and analyze their dynamics. Thirteen research fronts were identified in this sub-network. The biggest and oldest front is related to the clinical knowledge on the disease in the patient. Nine of the fronts are related to the study of specific molecular structures and mechanisms and two of these fronts are related to the development of drugs. The rest of the fronts are related to the study of the disease at the cellular level. Interestingly, the emergence of these fronts occurred in successive "waves" over the time which suggest a transition in the paradigmatic focus. The emergence and evolution of the biomedical fronts in HIV/AIDS research is explained not just by the partition of the problem in elements and interactions leading to increasingly specialized communities, but also by changes in the technological context of this health problem and the dramatic changes in the epidemiological reality of HIV/AIDS that occurred between 1993 and 1995.

Introduction

The Human Immunodeficiency Virus/ Acquired Immunodeficiency Syndrome (HIV/AIDS) is a global health problem: over 70 million people have been infected with HIV, 35 million have died and 36.7 million people currently live with the disease [ 1 ]. HIV/AIDS is one of the most studied infection diseases with more than 260,000 papers (mentioning the topic) listed in GOPubMed [ 2 ] and more than 42,000 papers (mentioning HIV/AIDS in the title) in the Web of Science [ 3 ] spanning over thirty year of scientific research. HIV/AIDS is studied by a plurality of biomedical disciplines like epidemiology [ 4 ], virology [ 5 ], immunology [ 6 ] or drug development [ 7 ] and non-biomedical disciplines like social sciences [ 8 ] and humanities [ 9 ]. All the biomedical disciplines working on HIV/AIDS strongly rely on a solid scientific consensus, which explains the clinical manifestation of HIV/AIDS in terms of the virus interactions with the immune system cells; the behavior and demography of the immune system cells, and, most importantly, the virus interaction with the biomolecular machinery of the host cells [ 10 – 12 ]. Two features are believed to be at the core of the scientific consensus on HIV/AIDS: the natural history of the HIV infection (the number of CD4+ cells and HIV RNA copies plotted over the time) [ 11 ] and the virus replication cycle (from the virus entry to the virus assembly, budding and maturation) [ 10 , 12 ].

Paradigms are the keystone of research communities [ 13 , 14 ], for they provide a foundation for members of the community; they also define the questions, the standards, the rules and the expected results that drive research efforts [ 13 , 14 ]. Paradigms of HIV/AIDS research are often presented in a timeline format [ 12 , 15 ]. However, while such a historical perspective is informative, they present two disadvantages: the first is that the selection of the most relevant discoveries is arbitrary, i.e., not supported by scientometric evidence, while the second disadvantage is that the paradigms are not presented as the key elements of the organizing process of the research communities.

The study of the emerging research fronts offers the possibility of analyzing the relationship between the paradigms and the organizational process of the scientific communities [ 14 , 16 , 17 ]. Research fronts can be considered as modules or clusters in a citation network of papers, i.e., sparse sub-networks of papers that exhibit dense connections [ 18 ].

It must be pointed out that research fronts are the footprint of the scientific communities. That is, citation patterns of scientists exhibit homophily [ 14 , 19 ], which is caused by the scientists trend to cite those papers that focus in similar topics with a similar approach -and very often they cite those papers that strengthen the papers argumentation [ 14 , 19 , 20 ]. Citations tend to point toward those discoveries that the research (sub)communities consider the most relevant ones. i.e., the paradigms [ 13 , 14 , 21 – 23 ]. Therefore, paradigms occupy the most central location in the citation networks; they are the seeds that organize the emergence of the research fronts [ 14 , 17 ]. To explain the emergence of the biomedical consensus on HIV/AIDS requires a study of the structure and dynamics of the research fronts.

Previous studies using the research fronts analysis approach were mainly focused in topics from engineering [ 24 , 25 ], biotechnologies [ 18 ] and scientometrics [ 26 ]. There are some studies that focused in the structure of the biomedical knowledge on specific diseases [ 14 , 16 , 17 , 27 , 28 ]. Our previous research has been particularly focused in the core region of the literature networks [ 14 , 17 , 27 ]. By doing this we have discovered the key feature of the organization of the knowledge on cervical cancer [ 27 ] and Ebola fever [ 17 ]. Others have reported the evolution of research fronts in anthrax research [ 16 ], cancer research [ 28 ] and cardiovascular medicine [ 28 ]. By analyzing the structure and evolution of HIV/AIDS knowledge we further our understanding of the nature of the biomedical knowledge discovery.

Through a combination of text mining and network analysis, we sought to understand the emergence and evolution of the research fronts (the footprints of the research communities) that produced the paradigmatic explanation of this disease.

Methodology

• A search of papers on HIV/AIDS was performed in the Web of Science [ 3 ] during March, 2017. The search criteria were the following: TITLE: ("HIV AIDS") OR TITLE: ("Human immunodeficiency virus") OR TITLE: ("acquired immune deficiency syndrome") OR TITLE: (hiv-1). Refined by: DOCUMENT TYPES: (ARTICLE). Timespan: All years. Indexes: SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI. 60,464 papers were found.
• A network model was built with the papers found in the Web of Science by using the software HistCite [ 29 ]. Then, the network model was analyzed and visualized with Cytoscape [ 30 ]. The indegree distribution of the network was evaluated to determine if it fitted to a power law function (y = ax^b).
• A core sub-network of papers with an indegree ≥ 28 was then closely examined. Normally, the indegree distribution in citation networks follows a power law function such that only a few papers are very well cited, while most papers are not [ 31 ]. This applies to the case of HIV/AIDS research as we report. We selected the papers with an indegree ≥ 28 because they are a small and workable quantity of papers that account for nearly half of the communication process through the citations network as it is reported in the results section (The selected papers received 42,8911 out of 679,497 citations from the HIV/AIDS literature). Top cited papers appear related to the paradigmatic milestones of a particular research topic.
• A cluster analysis based in the Newman modularity [ 32 ] was performed on the core sub-network using Clust&see, a Cystoscape plug-in [ 33 ]. This analysis divided the sub-network of citation in several research fronts (clusters or modules of papers). This clusters are defined by Newman as “groups of vertices within which connections are dense but between which they are sparse” [ 32 ].
• The sub-network was displayed by using the “yFiles organic” algorithm, which is based on the force-directed layout [ 30 ]. This algorithm considers the nodes as charged particles that exhibit repulsive forces and the vertices as springs. In this layout, the papers that cite the same papers tend to stick together making easier the visualization of the research fronts.
• The number of papers of each research front was plotted over the years in order to track the dynamics of the research fronts.
• The content of the identified research fronts -the abstract of their papers- was analyzed with KH Coder [ 34 ], a software for quantitative content analysis (Text mining). KH Coder delivered several outputs. However, we considered that the most informative output was the list of the most distinctive words which provided key information about what was the main focus of the papers of each front. Additionally, the five papers with the highest indegree within each of the research fronts were identified. in order to provide a context to the reading of the text mining results.
• Because front 1 “patient” is the largest and most central front according to our results, a cluster analysis was then performed on it by using Clust&see. The sub-modules that form front 1 were identified.

The network model

60,464 published articles on HIV/AIDS were identified by keyword search over the Thomson Reuters Web of Science. 57,485 of these papers form a single network of 679,497 inter-citations. The structural network analysis performed by Cytoscape showed that the distribution of the indegree in this network fitted a power law function (y = ax^b, a = 51,954, b = -1.79, correlation = 0.827, R-squared = 0.909). This means that a very small number of papers receive the overwhelming majority of citations while most papers receive few if any citations [ 31 , 35 ].

We selected papers with an indegree ≥ 28, that is, 5,933 documents. Together, these papers receive 63% of the inter-citations that form the whole network (42,8911 of 679,497), and would represent a relevant part of the historical core of the HIV/AIDS research as it was explained in the methodology section. These 5,933 highly cited papers formed a network of 86,963 inter-citations ( Fig 1 ). The cluster network analysis identified fourteen clusters (or modules as defined by Newman). However, one cluster were too small to be considered relevant research fronts. The thirteen clusters were formed by 12,303, 9,115, 7,407, 6,746, 5,680, 4,763, 4,696, 3507, 2,861, 2,768, 2,597, 2,053, and 1,662 inter-citations.

The model is displayed by using the “yFiles organic” algorithm. The color of nodes (representing the papers) and vertices indicates which research front they belong to.

The organization and dynamics of the research fronts

The main interaction among the seven research fronts is shown in Fig 2 . In this figure, each of the research fronts is represented by a single node, and the edges represent the sum of the inter-citations among the fronts ( Fig 2 ). Therefore, this graphical synthesis allows us to understand how the paradigmatic core of HIV/AIDS research was organized. However, the complete panorama can be only understood when Fig 2 is simultaneously read with Fig 3 and with Table 1 and S1 Table . Fig 3 shows the dynamics of the research fronts by plotting the number of citation papers per year of each research. In Fig 3 , the fronts are shown in different plots according to the period of time in which the fronts reached their maximum number of papers per year: between 1990 and 1991 ( Fig 3A ), between 1996 and 1999 ( Fig 3B ), and between 2004 and 2007 ( Fig 3C ). S1 Table provides the detailed description of each research front, including its structural features; the main topics of each research fronts according to the text mining analysis, and the list of the papers with the highest indegree within each research front. Table 1 groups the fronts according to the organization level (Individual, cellular-tissular and molecular) and the period in which the number of papers of each front peaked. The figures and the tables together offer an interesting view of the evolution and organization of HIV/AIDS research in the three first decades:

Each node represents one of the seven research fronts. The edges represent the sum of the inter-citations between two clusters. Only the interactions formed by a minimal of 500 inter-citations or the largest interaction (If the front have none interaction ≥ 500 inter-citations) of each front are shown.

A: Research fronts whose number of papers peaked between 1990 and 1991, B: peaked between 1996 and 1999 and C: peaked between 2004 and 2007.

HIV/AIDS research is reductionistly-organized, following a hierarchy of biological structures and systems ( Fig 2 , Table 1 ). That is, at the core of the network is located the front 1 “patient” (Figs ​ (Figs1 1 and ​ and2) 2 ) which focus on the study of the HIV/AIDS phenomenon at individual-systemic level. Surrounding front 1, there are research fronts (Front 3 “isolate,” front 9 “Cytotoxic T lymphocyte” and front 10 “brain” in Fgs 1 and 2) that are related to the study of specific events of the disease at cellular level ( Table 1 and S1 Table ). In the most external part of the network model there are most of the fronts related to the study of molecular structures and mechanisms (Front 5 “reverse transcriptase inhibitor” front 6 “assembly,” front 7 “protease inhibitor” front 8 “integration,” front 11 “replication,” front 12 “nucleocapsid” front and 13 “infectivity”; see Figs ​ Figs1 1 and ​ and2 2 and Table 1 and S1 Table ). On the other hand, Front 2 “glycoprotein 120” and front 5 “reverse transcriptase inhibitor” are strongly connected to front 1 “patient” (Figs ​ (Figs1 1 and ​ and2) 2 ) However, the research in these fronts (2 and 5) is oriented to the development of treatments (immuno-therapies and small molecules drugs, respectively), which may explain their strong connection to front 1. Notice that fronts 3 and 2 function as transition zones in HIV/AIDS research connecting the different levels of observation (systemic, tissular-to-cellular and molecular) (Figs ​ (Figs1 1 and ​ and2 2 ).

On the other hand, the research fronts clearly can be grouped in three different periods of time in which the fronts reach their maximum number of papers per year: 1990–1991, 1996–1999 and 2004–2007 ( Fig 3 ). In order to properly read Fig 3 it is important to keep in mind the dramatic changes in the epidemiology of HIV/AIDS in the United States (USA) that happened between 1993 and 1995 [ 36 ]. In that period, the number of AIDS diagnosis and deaths reached their maximum and then declined[ 36 ]. Simultaneously, in 1995, the number of persons living with HIV began to rise[ 36 ]. Therefore, we can consider the existence of two stages in the history of HIV/AIDS: before 1995 in which AIDS was the main concern and after 1995 when HIV infection is at the center of HIV/AIDS research. A second important consideration to understand Fig 3 is that the phase of expansion or growth in science (the “normal” science of Thomas Kuhn) follows the publication of those scientific achievements that organize the subsequent research[ 13 ]. This would explain that the peaks in Fig 3 generally occurred years after the publication of the papers with the highest degree ( Fig 3 and S1 Table ). The peaks in figure can be considered a delayed response to fundamental events and discoveries in the history of HIV/AIDS research. A third consideration is that the network model is made from the ten percent of papers with the highest indegree. Therefore, the succession of research fronts observed in Fig 3 does not mean the end of the research on specific topics but that these topics are not longer in the core of HIV/AIDS research.

Fronts 2 “glycoprotein 120,” 4 “tat-tar,” 5 “reverse transcriptase inhibitor” and 10 “brain” emerged immediately after front 1 and peaked in the 1990 and 1991 years. The expansion of these fronts in this early stage in the history of HIV/AIDS research suggests that these fronts are relevant to the description, explanation or intervention of AIDS. For example, it has been pointed out that tat (Trans-activator of transcription) protein, which is essential for virus replication, could be involved in the progression to AIDS and in the development of Kaposi's sarcoma lesions.[ 37 , 38 ] Along the same line, the interaction between glycoprotein 120 and CD4 is the first event in the replication cycle and is considered fundamental to virus entry.[ 39 ] It is important to keep in mind that the depletion of lymphocytes expressing CD4 is considered the most severe hematological feature of AIDS.[ 39 ] Similarly, encephalopathy is one of the most dominant feature of AIDS.[ 40 ] Finally, a reverse transcriptase inhibitor, zidovudine (AZT) was the first drug approved by the United States Food and Drug Administration (FDA) to treat AIDS.[ 41 ]

Research fronts 1 “patient,”and 3 “isolate,” reached their maximum number of papers per year between 1996 and 1999 ( Fig 3 ). The peaks of these fronts follow the changes in the epidemiology of HIV/AIDS in the USA. Therefore, these fronts are possibly related to a collective response from the scientific community to the new reality of the disease. The research in front 1 is the largest, central and most clinical among the fronts (Figs ​ (Figs1 1 and ​ and2, 2 , and S1 Table ). This front connects the clinical and epidemiological manifestations of HIV/AIDS with their explanation at a cellular level. Because of the size, the centrality and clinical relevance, we decided to perform a second round of cluster analysis to identify the sub-modules that may conform front 1. We plotted the contribution of each sub-module to the evolution of front 1 in Fig 4 . Sub-module 1A, 1D and 1E are the key components of the 1999's peak ( Fig 4 ). The papers with the highest indegree in sub-modules 1A, 1D and 1E are, respectively, “Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment,”[ 42 ] “Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection”[ 43 ] and “Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy”.[ 44 ] These papers report and explain fundamental changes in the clinical reality of HIV/AIDS produced by the implementation of anti-retroviral therapies. Front 3 “isolate,” to the study of HIV tropism, i.e., the differential capacity of the HIV strains to infect and replicates in different cell types ( Table 1 ). Importantly, the availability of screening tools that allowed the identification of asymptomatic individuals infected with HIV and the use of anti-retroviral therapies make extensively available the blood and tissue samples from the patients that were fundamental to the emergence of front 3.

On the other hand, most of the research fronts specialized in the study of specific molecular mechanisms and structures (fronts 6 to 9 and fronts 11 to 13) peaked either in the 1996–1999 or 2004–2007 periods ( Fig 3 ). It is important to notice that all these fronts emerged at the end of the first decade of HIV/AIDS research. The difference between fronts peaking in the second and the third periods is that the former decline earlier. In order to understand the evolution of these fronts is important to keep in mind that the scientific specialization is a continuous process of solving problems that follows the establishment of a paradigm (HIV-1 as the etiological agent of HIV/AIDS).[ 13 ] In that sense, the decline of fronts 8, 11 and 12 ( Fig 3B ) may be so because the scientific problem is either essentially solved or the changes in the HIV/AIDS epidemiology made less relevant the topics related to these fronts.

According to the Cytoscape analysis, the network of HIV/AIDS papers displays a power law distribution of their citations, which has important methodological implications. The first implication is that a research front (a citation network module) could be formed by other research fronts, which in turn can be partioned into sub-modules [ 44 ]. The second implication is that the nodes (papers) with the highest indegree tend to be more “cosmopolitan” i.e., they have the lowest clustering coefficient values [ 44 ]. That is, they could belong simultaneously to several fronts or any of them. Therefore, there are not clearly defined frontiers dividing the research fronts. However, the standard in the scientometrics study of research fronts seems to be to use clustering methods that define frontiers between the modules [ 14 , 17 , 18 , 24 , 25 , 27 , 28 ], probably because this is make much more understandable the community structure in a literature network. Moreover, our analysis reveals the front that is most relevant to each paper. Finally, the most important implication is that in a hierarchical literature network the most the papers with the highest indegree are related with the paradigms that organize a research field or topic [ 14 ]. Top cited papers have been extensively used to identify the scientific achievements that establish the standards of research practice of a particular community [ 14 , 17 , 22 , 23 , 27 , 28 , 45 , 46 ]. There are no set guidelines on the proportion of top cited papers that should be selected. However, there is a trade off between selecting the most informative papers and maintaining diversity of the information [ 14 , 17 ]. In this work, we used a minimal indegree of 30 to select the top cited papers, and in turn obtaining a considerable percentage of the citations. The selected papers consist of only ten percent of the network but they effectively account for two thirds of the citations. The selected papers are a reasonable representation of the paradigmatic core of HIV/AIDS research.

Once the HIV was recognized as the etiological factor HIV/AIDS research entered in normal science mode that is characterized by a high productivity and for a specialization of the researchers. By specialization we refer to “concentrate exclusively upon the subtlest and most esoteric aspects of the natural phenomena that concern his group” [ 12 ]. Once the paradigms are established, researchers focus on the details, the smaller range problems and solutions that the current paradigm provide [ 13 ]. Our results suggest that the emergence of several of the specialized research fronts was caused by the partition of the general problem in interacting elements. That is, HIV/AIDS research could be understood to some extent as a particular instance of part-whole science in which paradigms determine the abstraction of the parts that are considered the most relevant to explain the whole phenomenon [ 47 , 48 ].

The general structure and evolution of the research fronts in HIV/AIDS research shares similarities to that of anthrax and Ebola. The evolution of anthrax investigation began with a preliminary on the immunology of the disease [ 16 ]. From this, four research fronts emerged: “anthrax gene sequencing”, “vaccine research”, secondary research on PA (protective antigen) and LF (lethal factor), and “making and purifiying toxin” [ 16 ]. Subsequently, the research front on PA and LF split in three fronts: “specific PA research”, PA mediated delivery of other substances” and specific “LF research” [ 16 ]. Similarly, the evolution of the fronts in Ebola research are marked by a front related to the report of the epidemiology and the clinical manifestation of the disease [ 17 ]. A second front provide an explanation of the disease at tissue-cellular level [ 17 ]. Then, research on Ebola split into four research fronts, each one specialized in one different virus protein [ 17 ]. There is also a front aimed to the development of vaccines and other immunotherapies [ 17 ]. Similarly, the emergence of the fronts in HIV/AIDS research started with a general research front that provided the pathology of the disease and subsequently split into specialized fronts focused on the study of specific molecular mechanism of the virus replication cycle. In all three cases, the specialization of the research led to the emergence of research fronts focused in the study of the parts that are thought to be key in explaining the diseases. A report on the emergence of the research fronts in cancer and cardiovascular diseases showed that the specialization process in these types of diseases is complex [ 28 ]. Jones et al. reported fronts specialized on microarrays, targeted therapies, clinical trials, epidemiology and molecular etiology in cancer research [ 28 ], while in cardiovascular diseases the fronts are organized around drug-eluting stents, anti-platelet agents, pacemakers, hypertension and atrial fibrillation [ 28 ]. The difference between these two groups of diseases is that HIV/AIDS, anthrax and Ebola are infectious diseases with a clearly identified etiological agent while cancer and cardiovascular diseases are both complex multifactorial diseases [ 49 ].

This is the first time that the complex organization (and the evolution) of HIV/AIDS research is reported. Our research provides fundamental knowledge concerning the emergence of the paradigmatic explanation for HIV/AIDS and therefore makes a contribution to the understanding of the nature of biomedical knowledge. In addition, our work suggests that the development of the paradigmatic knowledge on HIV/AIDS in terms of the emergence and evolution of the research fronts followed two different routes. First, the emergence of the specialized fronts (molecular mechanism and structures and cellular process) was caused by the division of the general problem in their key process, element and interactions, which is related to the concept of part-whole science. Second, the dynamics of the fronts, particularly the evolution of front 1 “patient” and 2 “isolate”, appears to represent an adaptive and collective response from the scientific community to changes in the epidemiological (the decline in the morbidity and mortality of AIDS in the USA) and technological (the availability of treatments and screening tools) context of this health problem.

Supporting information

Structural properties; top 10 distinctive worlds, and list of the five papers with the highest indegree within each of the research fronts.

Funding Statement

The authors received no specific funding for this work.

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