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The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted persons with human immunodeficiency virus (HIV), interfering with critical health services for HIV prevention, treatment, and care. While there are multiple profiles of persons living with HIV and the impact of COVID-19 may differ for each, the severity of COVID-19 in persons with HIV is related strongly to the presence of comorbidities that increase the risk of severe disease in COVID-19 patients in the absence of HIV. An effective response to the juxtaposition of the HIV and COVID-19 pandemics requires a novel coordinated and collaborative global effort of scientists, industry, and community partners to accelerate basic and clinical research, as well as implementation science to operationalize evidence-based interventions expeditiously in real-world settings. Accelerated development and clinical evaluation of prevention and treatment countermeasures are urgently needed to mitigate the juxtaposition of the HIV and COVID-19 pandemics.

Four Decades of HIV/AIDS Considering the spectacular scientific advances that have been made over nearly four decades, it is conceivable that with optimal implementation of available prevention str...

Anthony Fauci on four decades of progress against HIV, and what’s needed for the future. Anthony Fauci on four decades of progress against HIV, and what’s needed for the future.

This article outlines the significant scientific progress reported in 2019 that has led to the development of new drugs and therapeutic regimens, vaccine candidates, and diagnostics for the prevention and treatment of tuberculosis. In 2020, it will be important to build on this momentum and continue to advance basic and clinical research to develop improved tools and interventions, simultaneously optimizing their implementation in national control programs. To successfully achieve the goal to end tuberculosis within a generation, a concerted, collective, and collaborative effort is required, involving government, academia, industry and civil society at all levels.

Eastern Equine Encephalitis Virus In the summer and fall of 2019, nine U.S. states reported 36 human cases (14 of them fatal) of EEE, an arthropod-borne viral (arboviral) disease transmitted by mos...

A converging public health crisis is emerging because the opioid epidemic is fueling a surge in infectious diseases, such as human immunodeficiency virus infection with or without AIDS, the viral hepatitides, infective endocarditis, and skin and soft-tissue infections. An integrated strategy is needed to tailor preventive and therapeutic approaches toward infectious diseases in people who misuse and/or are addicted to opioids and to concurrently address the underlying predisposing factor for the infections—opioid use disorder. This commentary highlights the unique and complementary roles that the infectious diseases and substance use disorder communities can play in addressing this crisis of dual public health concerns.

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4β7 with an anti-α4β7 monoclonal antibody (Rh-α4β7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4β7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4β7 or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α4β7 and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α4β7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.

Amid the staggering amount of suffering and death during this historic pandemic of COVID-19, a remarkable success story stands out. The development of several highly efficacious vaccines against a previously unknown viral pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in less than 1 year from the identification of the virus is unprecedented in the history of vaccinology. A frequently asked question is how such an extraordinary accomplishment could have been realized in such a short time frame, when timelines for other vaccines are measured in years if not decades. In fact, concern about this truncated timeline has contributed in part to the hesitancy in accepting these vaccines. What is not fully appreciated is that the starting point of the timeline for SARS-CoV-2 vaccines was not 10 January 2020, when the Chinese published the genetic sequence of the virus. Rather, it began decades earlier, out of the spotlight. Two activities predate the successful COVID-19 vaccines: the utilization of highly adaptable vaccine platforms such as RNA (among others) and the adaptation of structural biology tools to design agents (immunogens) that powerfully stimulate the immune system. The RNA approach evolved over several years owing to the ingenuity of individual scientists, including Drew Weissman and Katalin Kariko, and the concentrated efforts of several biotech and pharmaceutical companies. The discovery of an immunogen adaptable to the multiple platforms (messenger RNA and others) used for COVID-19 vaccines resulted from collaboration across different scientific subspecialities. At the Vaccine Research Center (VRC) of the U.S. National Institute of Allergy and Infectious Diseases, a group led by Peter Kwong had for several years used tools of structure-based vaccine design to determine the optimal structural conformation of a trimeric protein on the surface of the virus (the envelope protein) that allows HIV to bind to cells and ultimately trigger the production of antibodies that neutralize many HIV viral strains. Although this sophisticated approach has not yet led to a successful HIV vaccine, it caught the attention of another VRC investigator, Barney Graham, who was interested in generating a vaccine for respiratory syncytial virus (RSV). Graham joined Jason McLellan (of Kwong's team) to adapt a structure-based approach to an RSV vaccine. They identified the prefusion conformation of the viral spike protein as highly immunogenic and created mutations to stabilize that conformation for successful use as an immunogen. This was a huge step toward the creation of a successful RSV vaccine. VRC researchers and colleagues then built on the RSV advances. Graham's team, including Kizzmekia Corbett, and collaborators in the laboratories of McLellan and Andrew Ward adopted this approach of mutational stabilization of prefusion proteins in their work on the spike protein of the coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). So, when the genetic sequence of the SARS-CoV-2 became available, Graham's team lost no time in joining their long-time collaborators at Moderna to develop an RNA vaccine using a stabilized, prefusion spike protein as the immunogen. Pfizer and BioNTech, where Kariko was working, also used the RNA platform that she and Weissman had perfected and the immunogen designed by Graham to develop an RNA vaccine. Additional companies also used Graham's immunogen in other vaccine platforms that had been evolving for years, to make SARS-CoV-2 vaccines. SARS-CoV-2 vaccines based on the new immunogen rapidly moved to clinical trials. Several of these vaccines were tested in phase 3 efficacy trials at a time when the level of community spread of SARS-CoV-2 was extremely high, allowing vaccine efficacy endpoints of greater than 90% to be reached in a timely fashion. The speed and efficiency with which these highly efficacious vaccines were developed and their potential for saving millions of lives are due to an extraordinary multidisciplinary effort involving basic, preclinical, and clinical science that had been under way—out of the spotlight—for decades before the unfolding of the COVID-19 pandemic. When the stories and recounting of this pandemic are written, it is important that this history not be forgotten, as we are reminded once again of the societal value of a sustained and robust support of our scientific enterprise.

Summary Infectious diseases prevalent in humans and animals are caused by pathogens that once emerged from other animal hosts. In addition to these established infections, new infectious diseases periodically emerge. In extreme cases they may cause pandemics such as COVID-19; in other cases, dead-end infections or smaller epidemics result. Established diseases may also re-emerge, for example by extending geographically or by becoming more transmissible or more pathogenic. Disease emergence reflects dynamic balances and imbalances, within complex globally distributed ecosystems comprising humans, animals, pathogens, and the environment. Understanding these variables is a necessary step in controlling future devastating disease emergences., Understanding the dynamic balance and interplay between complex and global ecosystems comprising humans, animals, pathogens, and the environment provides perspectives on how we got to the COVID-19 pandemic.

___Key messages___ The Commission recommends five priority investments to achieve a tuberculosis-free world within a generation. These investments are designed to fulfil the mandate of the UN High Level Meeting on tuberculosis. In addition, they answer the question of how countries with high-burden tuberculosis and their development partners should target their future investments to ensure that ending tuberculosis is achievable. __Invest first to ensure that high quality rapid diagnostics and treatment are provided to all individuals receiving care for tuberculosis, wherever they seek care__ This priority includes rapid drug susceptibility testing and second-line treatment for resistant forms of tuberculosis. Achieving universal, high-quality person-centred and family-centred care—including sustained improvement in the performance of private sector providers—usually should be the top policy and budget priority. __Reach people and populations at high risk for tuberculosis (such as household and other close contacts of people with tuberculosis, and people with HIV) and bring them into care__ Active case-finding and treatment in high-risk populations demands adequate resources to reach and care for these populations. At the same time, reaching certain high-risk populations, such as people co-infected with tuberculosis and HIV, for tuberculosis preventive therapy is essential to achieve epidemiologic control. Once high-risk populations have access to affordable, high-quality diagnostic, treatment and preventive services, invest in identifying tuberculosis cases in the general population, primarily by strengthening the capacity to deliver health services and move toward universal health coverage. __Increase investment to accelerate tuberculosis research and development and bring new diagnostics, therapeutic strategies, and vaccines to clinical practice to quickly end the pandemic__ Strong advocacy with science ministries and research-oriented pharmaceutical companies is crucial, including ministries and companies in middle-income countries, to highlight the importance of investing in new tools. Financing the early uptake of new products will provide important confidence signals to product developers. __Make investment in tuberculosis programmes a shared responsibility, increasing development assistance for tuberculosis according to the financial needs of individual low-income and middle-income countries__ As countries successfully mobilise more domestic resources towards tuberculosis programmes, external assistance to middle-income countries should address the following priorities: reduce the spread of drug-resistant tuberculosis in all affected low-income and middle-income countries; facilitate market-shaping activities to enable access to high quality drugs and diagnostics for high-burden countries; and finance tuberculosis research and development, including product development as well as population, policy, and implementation research that will provide lessons and international sharing of best practices. __Hold countries and key stakeholders accountable for progress made towards ending tuberculosis__ Accountability entails establishing independent, multisectoral processes, such as national tuberculosis report cards, to ensure that all stakeholders carry out their responsibilities to contribute to ending the pandemic. Accountability mechanisms should not only assess progress, but also guarantee that Heads of Governments, national tuberculosis programmes, and even regional and site-level clinics, as well as key non-governmental organisations, take the necessary corrective actions to remove obstacles to ending tuberculosis.

In sharp contrast to viruses such as measles, in which a single exposure generates long-lasting immunity, individuals are repeatedly exposed to influenza viruses throughout their lifetime without developing broad and durable protection against infection. As a consequence, substantial worldwide

This article highlights biomedical research goals for the development of critical tools, including innovative diagnostics, safe and effective vaccines, and new and improved therapeutics, necessary to achieve an end to the global epidemic of sexually transmitted infections. The incidence of sexually transmitted infections (STIs), including gonorrhea, syphilis, chlamydia, and trichomoniasis, is increasing by over 1 million new cases daily and represents a global public health crisis. There is an alarming increase of gonorrhea and syphilis among men who have sex with men and bisexual men, 2 key populations also at high risk for human immunodeficiency virus. A refocused, dedicated, and intensive biomedical research program is needed targeting development of innovative diagnostics, safe and effective vaccines, and new and improved therapeutics. This article highlights biomedical research goals providing critical tools necessary to achieve an end to the global STIs epidemic.

The goal of ending the HIV/AIDS pandemic is theoretically achievable and would require addressing this global health catastrophe on individual and global levels by providing optimal prevention strategies and treatment regimens for individual persons living with or at risk for HIV, as well as ending the pandemic as an epidemiologic and global health phenomenon. However, from a practical standpoint, the pathway to ending the HIV/AIDS pandemic will be difficult and will require aggressive implementation of the biomedical research advances that have been made in the areas of treatment and prevention; development of additional tools, such as a moderately effective HIV vaccine; and attention to critical behavioral and social determinants. An end to the HIV/AIDS pandemic can be achieved only with provision of sustained and additional resources at the local, regional, national, and global levels.

Purpose of Review Acute HIV infection is characterized by high-level viral replication throughout the body’s lymphoid system, particularly in gut-associated lymphoid tissues resulting in damage to structural components of gut tissue. This damage is irreversible and believed to contribute to the development of immune deficiencies. Antiretroviral therapy (ART) does not restore gut structure and function. Studies in macaques point to an alternative treatment strategy that may ameliorate gut damage. Integrin α4β7 mediates the homing of lymphocytes to gut tissues. Vedolizumab, a monoclonal antibody (mAb) antagonist of α4β7, has demonstrated efficacy and has been approved for the treatment of inflammatory bowel disease in humans. Here, we describe our current knowledge, and the gaps in our understanding, of the role of α4β7 in HIV pathogenesis and treatment. Recent Findings When administered to macaques prior to infection, a nonhuman primate analogue of vedolizumab prevents transmission of SIV. In combination with ART, this mAb facilitates durable virologic control following treatment interruption. Summary Targeting α4β7 represents a novel therapeutic approach to prevent and treat HIV infection.

Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4β7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4β7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4β7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4β7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of

VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4β7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4β7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4β7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4β7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4β7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4β7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies., Author summary Broadly neutralizing antibodies (bNAbs) constitute a promising new strategy to prevent and/or treat HIV-1 acquisition. However, it is clear that individual bNAbs cannot be used alone as a single intervention. α4β7 blockade with a monoclonal antibody (mAb) similar to a drug approved for treatment of inflammatory bowel disease (IBD) has shown promising results against SIV infection in non-human primate studies. In the current study, we report the impact of combining the bNAb VRC01, currently in clinical testing for HIV-1 prevention, with the anti-α4β7 mAb on delaying infection of macaques with a pathogenic simian/human immunodeficiency virus (SHIV). We found that the VRC01/anti-α4β7 combination was able to significantly delay SHIV acquisition when compared with the control group, but not when compared with pretreatment with VRC01 alone. Moreover, after infection, the animals pretreated with the VRC01/anti-α4β7 combination had higher CD4 counts compared to the other treatment groups and lower amounts of virus in the gut compared to the control group. Moreover, important differences were present between the groups in the immune response to the virus in blood and mucosal tissues. More studies are needed to explore the potential synergistic effects of combining bNAbs with the α4β7 blockade for the prevention and therapy of HIV-1 infection.

Measles in 2019 — Going Backward Recent increases in measles cases in the United States mirror patterns in other countries that had previously eliminated the virus. This resurgence is all the more frustrating since the disease is entirely preventable through vaccination.

Controlling and ultimately ending tuberculosis (TB) as a public health scourge will require a multifaceted and comprehensive approach involving the intensification of public health efforts, including scaling-up the delivery of current diagnostic, preventive, and therapeutic tools. However, a critically important element in the effort to end TB is an accelerated biomedical research effort to address the many unanswered questions about the disease process itself and to develop improved and innovative countermeasures. An intensive effort toward these research goals will facilitate the achievement of the aspirational goal of ending TB.

PEPFAR — 15 Years and Counting the Lives Saved Launched in 2003, the President’s Emergency Plan for AIDS Relief has had a major impact on the HIV/AIDS pandemic. Support for the program should continue, allowing it to serve as a model for the control and elimination of other devastating infectious diseases.

Sylvatic transmission cycles of yellow fever continue to occur in endemic tropical regions. If the outbreak in Brazil leads to urban spread, U.S. clinicians should adopt a high index of suspicion for the disease, particularly in travelers returning from affected areas.

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.

BACKGROUND: Because HIV viral suppression is essential for optimal outcomes and prevention efforts, understanding trends and predictors is imperative to inform public health policy. OBJECTIVE: To evaluate viral suppression trends in people living with HIV (PLWH), including the relationship of associated factors, such as demographic characteristics and integrase strand transfer inhibitor (ISTI) use. DESIGN: Longitudinal observational cohort study. SETTING: 8 HIV clinics across the United States. PARTICIPANTS: PLWH receiving clinical care. MEASUREMENTS: To understand trends in viral suppression (≤400 copies/mL), annual viral suppression rates from 1997 to 2015 were determined. Analyses were repeated with tests limited to 1 random test per person per year and using inverse probability of censoring weights to address loss to follow-up. Joint longitudinal and survival models and linear mixed models of PLWH receiving antiretroviral therapy (ART) were used to examine associations between viral suppression or continuous viral load (VL) levels and demographic factors, substance use, adherence, and ISTI use. RESULTS: Viral suppression increased from 32% in 1997 to 86% in 2015 on the basis of all tests among 31 930 PLWH. In adjusted analyses, being older (odds ratio [OR], 0.76 per decade [95% CI, 0.74 to 0.78]) and using an ISTI-based regimen (OR, 0.54 [CI, 0.51 to 0.57]) were associated with lower odds of having a detectable VL, and black race was associated with higher odds (OR, 1.68 [CI, 1.57 to 1.80]) (P < 0.001 for each). Similar patterns were seen with continuous VL levels; when analyses were limited to 2010 to 2015; and with adjustment for adherence, substance use, or depression. LIMITATION: Results are limited to PLWH receiving clinical care. CONCLUSION: HIV viral suppression rates have improved dramatically across the United States, which is likely partially attributable to improved ART, including ISTI-based regimens. However, disparities among younger and black PLWH merit attention.

The explosive pandemic of Zika virus infection in South and Central America is the most recent of four unexpected arrivals of important arthropod-borne viral diseases in the Western Hemisphere over the past 20 years. Is this an important new disease-emergence pattern?

Despite substantial clinical benefits, complete eradication of HIV has not been possible using antiretroviral therapy (ART) alone. Strategies that can either eliminate persistent viral reservoirs or boost host immunity to prevent rebound of virus from these reservoirs after discontinuation of ART are needed; one possibility is therapeutic vaccination. We report the results of a randomized, placebo-controlled trial of a therapeutic vaccine regimen in patients in whom ART was initiated during the early stage of HIV infection and whose immune system was anticipated to be relatively intact. The objectives of our study were to determine whether the vaccine was safe and could induce an immune response that would maintain suppression of plasma viremia after discontinuation of ART. Vaccinations were well tolerated with no serious adverse events but produced only modest augmentation of existing HIV-specific CD4+ T cell responses, with little augmentation of CD8+ T cell responses. Compared with placebo, the vaccination regimen had no significant effect on the kinetics or magnitude of viral rebound after interruption of ART and no impact on the size of the HIV reservoir in the CD4+ T cell compartment. Notably, 26% of subjects in the placebo arm exhibited sustained suppression of viremia (

Eastern Equine Encephalitis Virus In the summer and fall of 2019, nine U.S. states reported 36 human cases (14 of them fatal) of EEE, an arthropod-borne viral (arboviral) disease transmitted by mos...

Several highly potent and broadly neutralizing monoclonal antibodies against HIV have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We show that several HIV-specific monoclonal antibodies--in particular, PGT121, VRC01, and VRC03--potently inhibited entry into CD4(+) T cells of HIV isolated from the latent viral reservoir of infected individuals whose plasma viremia was well controlled by ART. In addition, we demonstrate that HIV replication in autologous CD4(+) T cells derived from infected individuals receiving ART was profoundly suppressed by three aforementioned and other HIV-specific monoclonal antibodies. These findings have implications for passive immunotherapy as an approach toward controlling plasma viral rebound in patients whose ART is withdrawn.

While the human immunodeficiency virus (HIV)/AIDS pandemic continues, the incidence of HIV infections has fallen because of the deployment of antiretroviral drugs and multiple prevention modalities. To achieve a durable end to the pandemic, a vaccine remains essential. Recent advances in vaccinology offer new promise for an effective HIV vaccine.

Studies proving that the benefits of prompt initiation of antiretroviral therapy for HIV infection outweigh the risks and that preexposure prophylaxis can be implemented safely and effectively will serve as critical tools in the fight to end the HIV–AIDS pandemic.

Elite controllers suppress human immunodeficiency virus (HIV) viremia to below the limit of detection in the absence of antiretroviral therapy (ART). However, precise frequencies of CD4(+) T cells carrying replication-competent HIV and/or the dynamics of the infectious viral reservoirs in response to initiation and discontinuation of ART in elite controllers are unknown. We show that the size of the pool of CD4(+) T cells harboring infectious HIV diminished significantly after initiation of ART and rebounded to baseline upon cessation of therapy. Our data provide compelling evidence that persistent viral replication occurs in untreated elite controllers even in the absence of detectable plasma viremia.

Terminal differentiation of B cells and hypergammaglobulinemia are hallmarks of B-cell hyperactivity in HIV disease. Plasmablasts are terminally differentiating B cells that circulate transiently in the blood following infection or vaccination; however, in HIV infection, they arise early and are maintained at abnormally high levels in viremic individuals. Here we show that only a small fraction of plasmablasts in the blood of viremic individuals is HIV specific. Assessment of plasmablast immunoglobulin isotype distribution revealed increased IgG + plasmablasts in early and most prominently during chronic HIV viremia, contrasting with a predominantly IgA + plasmablast profile in HIV-negative individuals or in aviremic HIV-infected individuals on treatment. Of note, IgG is the predominant immunoglobulin isotype of plasmablasts that arise transiently in the blood following parenteral immunization. Serum immunoglobulin levels were also elevated in HIV-infected viremic individuals, especially IgG, and correlated with levels of IgG + plasmablasts. Several soluble factors associated with immune activation were also increased in the sera of HIV-infected individuals, especially in viremic individuals, and correlated with serum immunoglobulin levels, particularly IgG. Thus, our data suggest that while plasmablasts in the blood may contribute to the HIV-specific immune response, the majority of these cells are not HIV specific and arise early, likely from indirect immune-activating effects of HIV replication, and reflect over time the effects of chronic antigenic stimulation. Such B-cell dysregulation may help explain why the antibody response is inadequate in HIV-infected individuals, even during early infection.

The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART).We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART.A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 μg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus.VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).

Antibodies sustain viral control For many infected individuals, antiretroviral therapy (ART) means that an HIV-1 diagnosis is no longer a death sentence. But the virus persists in treated individuals, and complying with the intense drug regimen to keep virus loads down can be challenging for patients. Seeking an alternative, Byrareddy et al. treated ART-suppressed monkeys with antibodies targeting α4β7 integrin. When ART was halted in the antibody-treated animals, viral loads stayed undetectable, and normal CD4 T cell counts were maintained for over 9 months—and persisted—even after stopping the antibody therapy. Science , this issue p. 197 Update: An Editorial Expression of Concern has been published here

The extraordinary scientific advances made in the past three decades to understand, treat, and prevent HIV infection have contributed to the hope that a world free of AIDS is achievable. The growing armamentarium of scientifically proven interventions-including the use of antiretroviral medications to treat and prevent HIV infection, voluntary medical male circumcision, education and counseling about HIV risk and behavior change, condom use, drug and alcohol treatment, and needle exchange programs for injection drug users-offers an unprecedented opportunity to make major gains in the fight against HIV/AIDS. Combining and implementing these interventions as effectively as possible has the potential to dramatically change the trajectory of the HIV/AIDS pandemic. Substantive challenges remain, especially obtaining sufficient funding for HIV-related interventions and developing the operational capacity to deliver them cost-effectively to all in need. If these challenges can be met, the world will have a clear path toward an "AIDS-free generation" in which new HIV infections, as well as illness and death due to AIDS, are increasingly rare.

Residual plasma viremia (50 copies/mL) persists in certain human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART); however, the relationship between the degree of residual plasma viremia, the size of HIV reservoirs, and the level of immune activation has not been delineated. Here, we demonstrate that residual plasma viremia correlates with the size of the CD4(+) T cell viral reservoir, but not with markers of immune activation, suggesting that reactivation of the latent viral reservoir may not be the sole source of residual plasma viremia. Novel therapeutic strategies aimed at targeting the source of residual viremia may be necessary to achieve viral eradication.

Human immunodeficiency virus (HIV) infection is generally characterized by inefficient viral transmission; an acute phase of intense viral replication and dissemination to lymphoid tissues; a chronic, often asymptomatic phase of sustained immune activation and viral replication; and an advanced phase of marked depletion of CD4+ T cells that leads to acquired immune deficiency syndrome. Major insight into HIV transmission and each phase of infection has been gained from studies on blood and tissue specimens obtained from HIV-infected individuals, as well as from animal and ex vivo models. Not only has the introduction of effective antiretroviral therapy greatly diminished the morbidity and mortality associated with HIV disease progression, it has also provided new avenues of research toward delineating the mechanisms of HIV-induced pathogenesis. Further advances in therapeutics and informative technologies, combined with a better understanding of the immunologic and virologic components of HIV disease, hold promise for new preventative and even curative strategies.

The development of a safe and effective HIV vaccine is perhaps the most significant and challenging goal remaining in HIV/AIDS research. Recent progress using a poxvirus vector prime and envelope protein boost strategy demonstrated a modest but significant level of efficacy and for the first time established the concept that a vaccine could prevent HIV infection (1). Because protection waned over time, approaches to boost durability and efficacy are currently in the planning stages (2). In addition, alternative approaches, particularly those using adenovirus vectors with various HIV gene inserts have been evaluated. In this regard, between 2005 and 2013 two vaccine concepts based on recombinant Adenovirus serotype-5 (rAd5) were evaluated in three efficacy studies (3–5). The first study (Step) using 3 doses of the Merck rAd5-gag/pol/nef vaccine was stopped for futility; of note, a trend toward increased HIV infections in vaccine recipients was observed (3). Once the entire Step dataset accumulated from 18 months of blinded follow-up was analyzed, this trend became statistically significant (6). The Step study showed an overall increased risk of acquisition (HR 1.4, p< 0.03); however, the group at highest risk was uncircumcised men who both had sex with men (MSM) and had high levels of pre-existing Ad5 antibodies (HR 4.2, p=0.02) (6). Following the release of the Step findings, the Phamibili trial of the same Merck Ad5 vaccine platform conducted in South Africa, was closed and unblinded early during the enrollment period. Few Phamibili participants received the planned three doses of vaccine. Primary analysis of the Phambili follow up data showed no increased risk of HIV infection (5). However, data from the long term unblinded follow-up of Phambili participants suggested an increased risk of infection in vaccinated men compared to unvaccinated controls (7). In 2009, a different rAd5 vaccine platform advanced to efficacy testing in the HIV Vaccine Trial Network (HVTN) 505 trial. The vaccine contained 3 doses of a DNA prime followed by a single rAd5 boost with inserts expressing HIV envelope and viral structural antigens. As a safety precaution, this study restricted enrollment to circumcised MSM who lacked pre-existing Ad5 antibodies, since no level of increased risk had been seen in this group in the Step Trial (6). The HVTN 505 trial was halted prematurely because it met futility criteria; however, there was no evidence of increased risk of acquisition in the vaccinated subjects (8). Based upon this information, the National Institute of Allergy and Infectious Diseases (NIAID) convened the Mini-Summit on Adenovirus Platforms for HIV Vaccines on September 19, 2013 (9) to investigate: 1) if rAd5 vectors are associated with increased risk of HIV infection; and 2) whether these problems extend to some or all of the other recombinant adenovirus vectors currently in development. Additional goals were to evaluate possible mechanisms by which rAd vectors could increase susceptibility to infection. In addition, the question was raised whether increased susceptibility might be seen with any HIV vaccine that activates the immune system rendering activated CD4+ T cells more susceptible to HIV infection, while at the same time inducing little or no protective effect against HIV acquisition (9).

Characterization of lymphocytes including B cells during early versus chronic HIV infection is important for understanding the impact of chronic viremia on immune cell function. In this setting, we investigated B cells before and after reduction of HIV plasma viremia by antiretroviral therapy (ART). At baseline, peripheral blood B-cell counts were significantly lower in both early and chronic HIV-infected individuals compared with uninfected controls. Similar to CD4+ but not CD8+ T cells, B-cell numbers in both groups increased significantly after ART. At baseline, B cells of early HIV-infected individuals were composed of a higher percentage of plasmablasts and resting memory B cells compared with chronic HIV-infected individuals whose B cells were composed of a higher percentage of immature/transitional and exhausted B cells compared with their early infection counterparts. At 1 year after ART, the percentage of resting memory B cells remained higher in early compared with chronic HIV-infected individuals. This difference translated into a better functional profile in that memory B-cell responses to HIV and non-HIV antigens were superior in early- compared with chronic-treated HIV infected individuals. These findings provide new insights on B cells in HIV infection and how early initiation of ART may prevent irreversible immune system damage.

The American College of Rheumatology Subcommittee on Classification of Vasculitis of the Diagnostic and Therapeutic Criteria Committee developed classification criteria for 7 forms of vasculitis: polyarteritis nodosa, Churg-Strauss syndrome, Wegener's granulomatosis, hypersensitivity vasculitis, Henoch-Schönlein purpura, giant cell (temporal) arteritis, and Takayasu arteritis. The data collection methods, quality control, and analytic procedures used to derive the classification rules are discussed herein.

Criteria for identifying Henoch-Schönlein Purpura (HSP) and distinguishing HSP from other forms of systemic arteritis were developed by comparing the manifestations in 85 patients who had HSP with those of 722 control patients with other forms of vasculitis. By the traditional format of choosing different combinations of candidate criteria and comparing the combinations for their ability to separate HSP cases from controls, 4 criteria were identified: age less than or equal to 20 years at disease onset, palpable purpura, acute abdominal pain, and biopsy showing granulocytes in the walls of small arterioles or venules. The presence of any 2 or more of these criteria distinguish HSP from other forms of vasculitis with a sensitivity of 87.1% and a specificity of 87.7%. The criteria selected by a classification tree method were similar: palpable purpura, age less than or equal to 20 years at disease onset, biopsy showing granulocytes around arterioles or venules, and gastrointestinal bleeding. These were able to distinguish HSP from other forms of vasculitis with a sensitivity of 89.4% and a specificity of 88.1%.

Criteria for the classification of Takayasu arteritis were developed by comparing 63 patients who had this disease with 744 control patients with other forms of vasculitis. Six criteria were selected for the traditional format classification: onset at age less than or equal to 40 years, claudication of an extremity, decreased brachial artery pulse, greater than 10 mm Hg difference in systolic blood pressure between arms, a bruit over the subclavian arteries or the aorta, and arteriographic evidence of narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities. The presence of 3 or more of these 6 criteria demonstrated a sensitivity of 90.5% and a specificity of 97.8%. A classification tree also was constructed with 5 of these 6 criteria, omitting claudication of an extremity. The classification tree demonstrated a sensitivity of 92.1% and a specificity of 97.0%.

HIV viremia is associated with a wide range of immune dysfunctions that contribute to the immunocompromised state. HIV viremia has been shown to have a broad effect on several immune cell types and/or their interactions that are vital for mounting an effective immune response. In this study, we investigated the integrity of plasmacytoid dendritic cell (pDC)-NK cell interactions among HIV viremic, aviremic, and seronegative individuals. We describe a critical defect in the ability of pDCs from HIV-infected individuals to secrete IFN-alpha and TNF and subsequently activate NK cells. We also describe an inherent defect on NK cells from HIV-infected individuals to respond to pDC-secreted cytokines. Furthermore, we were able to demonstrate a direct effect of HIV trimeric gp120 on NK cells in vitro similar to that described ex vivo. Finally, we were able to establish that the HIV gp120-mediated suppressive effect on NK cells was a result of its binding to the integrin alpha(4)beta(7) expressed on NK cells. These findings suggest a novel mechanism by which HIV is capable of suppressing an innate immune function in infected individuals.

The US National Institute of Allergy and Infectious Diseases convened a workshop of malaria investigators and immunologists to foster collaborations and attract more immunologists into malaria research. Discussions highlighted research gaps and underscored the incomplete understanding of basic immune mechanisms that contribute to the pathogenesis of or protection against malaria.

Background. Untreated human immunodeficiency virus (HIV) disease leads to abnormalities in all major lymphocyte populations, including CD4 + T cells, CD8 + T cells, and B cells. However, little is known regarding the effect of antiretroviral therapy (ART)-induced decrease in HIV viremia on B cell numbers and subpopulations. Methods. We conducted a longitudinal study to evaluate changes in B cell numbers and subpopulations that occur during the course of 12 months of effective ART in a group of individuals with chronic HIV infection. Results. ART-induced decrease in HIV viremia was associated with a significant increase in B cell counts, similar to increases in CD4 + T cell counts yet distinct from the lack of increase in CD8 + T cells. The increase in B cell counts was accompanied by a significant decrease in the frequency of apoptosis-prone B cell subpopulations, namely mature activated and immature transitional B cells, which are overrepresented in untreated HIV disease. The increase in B cell counts was reflected by a significant increase in naive and resting memory B cells, both of which represent populations that are essential for generating adequate humoral immunity. Conclusions. Normalization of B cell counts and subpopulations may help to explain the improvement in humoral immunity reported to occur after an ART-induced decrease in HIV viremia.

Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM). To assess Ab reactivity in TLM and RM B cells, single-cell cloning was performed on HIV envelope CD4–binding site–sorted (CD4bs-sorted) B cells from 3 individuals with chronic HIV viremia. Several clonal families were present among the 127 cloned recombinant mAbs, with evidence of crosstalk between TLM and RM B cell populations that was largely restricted to non-VH4 families. Despite evidence of common origins, SHM frequencies were significantly decreased in TLM-derived mAbs compared with SHM frequencies in RM-derived mAbs. However, both cell populations had lower frequencies of SHMs than did broadly neutralizing CD4bs–specific mAbs. There was a significant correlation between SHM frequencies and the HIV-neutralizing capacities of the mAbs. Furthermore, HIV neutralization was significantly higher in the RM-derived mAbs compared with that seen in the TLM-derived mAbs, and both SHM frequencies and neutralizing capacity were lowest in TLM-derived mAbs with high polyreactivity. Thus, deficiencies in memory B cells that arise during chronic HIV viremia provide insight into the inadequacy of the Ab response in viremic individuals.