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The 2005 Immunity paper by Kariko et al. has been hailed as a cornerstone insight that directly led to the design and delivery of the mRNA vaccines against COVID-19. We asked experts in pathogen sensing, vaccine development, and public health to provide their perspective on the study and its implications.

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)–infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.

Purpose of review Trafficking of lymphocytes into and between gut inductive and effector sites of the gut tissues is regulated by integrin α4β7. Recent findings that describe the central role of α4β7 CD4 T cells in HIV pathogenesis, and the possibility of targeting these cells to prevent or treat HIV infection will be reviewed. Recent findings Recent reports indicate that the frequency of α4β7 CD4 T cells is directly correlated with the risk of HIV acquisition and CD4 T-cell decline post infection. MAdCAM -mediated signaling through α4β7, in the presence of retinoic acid, supports viral replication in recently activated naive CD4 T cells. Treatment of HIV-infected patients with vedolizumab, an α4β7 antagonist, is well tolerated, and reduces the size and number of lymphoid aggregates in gut associated lymphoid tissues. Summary Integrin α4β7 underlies one of the principal mechanisms that CD4 T cells employ to traffic to the gut. It also defines a subset of cells that play a significant role in HIV transmission and pathogenesis. Understanding how α4β7 facilitates gut homing may provide insight into key aspects of HIV transmission, pathogenesis, and the formation of viral reservoirs. Targeting α4β7 may have utility in the prevention and treatment of HIV infection.

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

Changes in the microbiota are associated with disease susceptibility, immune system development, and responses to treatment. Refocusing research to elucidate the causal links between the human microbiota and infectious and immune-mediated diseases will be critical to harnessing its power to prevent, diagnose, and treat such diseases.

Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4β7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with α4β7. Such costimulation promotes high levels of HIV replication. An anti-α4β7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α4β7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-α4β7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α4β7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.

Integrin α4β7 mediates the trafficking of leukocytes, including CD4+ T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin α4β7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and CD4+ cells in rhesus macaques infected with SIV. We determined that α4β7 mAb reduced viral antigen in an array of tissues of the lung, spleen, axillary, and inguinal lymph nodes. These sites are not directly linked to α4β7 mediated homing; however, the most pronounced reduction in viral load was observed in the colon. Despite this reduction, α4β7 mAb treatment did not prevent an apparent depletion of CD4+ T cells in gut in the acute phase of infection that is characteristic of HIV/SIV infection. However, α4β7 mAb appeared to facilitate the preservation or restoration of CD4+ T cells in gut tissues at later stages of infection. Since damage to the gut is believed to play a central role in HIV pathogenesis, these results support further evaluation of α4β7 antagonists in the study and treatment of HIV disease.

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.

Development of a universal influenza vaccine is a research priority for the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. To facilitate this goal, we convened a workshop in Rockville, Maryland to identify knowledge gaps in influenza research and develop strategies to fill them.

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.

Although extraordinary progress has been made in the treatment and prevention of HIV infection, the AIDS pandemic continues to rage globally with 2.1 million infections and 1.6 million AIDS-related deaths reported in 2013. Until an effective vaccine is developed, new strategies for treatment and prevention are needed. Regarding the prevention of HIV infection, a major focus of prevention research in general and vaccine research in particular involves the interaction of the HIV-1 envelope protein gp120 with cell-surface receptors, with the hope that a greater understanding of these interactions will lead to the development of novel strategies aimed at preventing and even treating HIV-1 infection. Particular attention has been directed toward gaining a more precise understanding of the early events in transmission focusing on that critical window of time when HIV first establishes infection in the host. Here we describe some of the recent findings involving HIV-1 envelope interactions with cell surface receptors that are relevant to transmission and which may represent new opportunities to develop strategies to prevent HIV infection.

The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin α4β7, a gut-homing receptor. Using both cell-surface expressed α4β7 and a soluble α4β7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of α4β7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4β7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4β7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4β7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4β7. It includes the canonical LDV/I α4β7 binding site, a cryptic epitope that lies 7-9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-α4β7 interactions. These mAbs recognize conformations absent from the β- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4β7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.

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 (1000TCID50) 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 the controls. Interestingly, VRC01-Rh-α4β7-treated macaques had less 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 anti-viral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and anti-viral immune responses is warranted and may lead to novel preventive and therapeutic strategies.Short summaryA combination of VRC01 and Rh-α4β7 significantly delayed SHIV acquisition, protected CD4 counts, decreased gut viral load and modified the immune response to the virus.

The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α4β7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α4β7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α4β7+ peripheral blood CD4+ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α4β7 binding. In addition, pre-HIV α4β7+ CD4+ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4+ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α4β7+ CD4+ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4+ T cells expressing α4β7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α4β7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α4β7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α4β7 integrin as a clinical intervention during HIV infection.

The intestinal mucosa is a key anatomical site for HIV-1 replication and CD4+ T cell depletion. Accordingly, in vivo treatment with an antibody to the gut-homing integrin α4β7 was shown to reduce viral transmission, delay disease progression, and induce persistent virus control in macaques challenged with simian immunodeficiency virus (SIV). We show that integrin α4β7 is efficiently incorporated into the envelope of HIV-1 virions. Incorporated α4β7 is functionally active as it binds mucosal addressin cell adhesion molecule-1 (MAdCAM-1), promoting HIV-1 capture by and infection of MAdCAM-expressing cells, which in turn mediate trans-infection of bystander cells. Functional α4β7 is present in circulating virions from HIV-infected patients and SIV-infected macaques, with peak levels during the early stages of infection. In vivo homing experiments documented selective and specific uptake of α4β7+ HIV-1 virions by high endothelial venules in the intestinal mucosa. These results extend the paradigm of tissue homing to a retrovirus and are relevant for the pathogenesis, treatment, and prevention of HIV-1 infection.

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.

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 .).

The ultimate goal of HIV cure research is to allow HIV-infected individuals to be free of disease in the absence of antiretroviral therapy. We discuss current directions and future opportunities aimed at achieving sustained virological remission, and possibly eradication. A multidisciplinary approach to HIV cure research will be important, and ethical, social and behavioural research should be conducted in parallel with basic and clinical research.

The humoral immune response after acute infection with HIV-1 is delayed and ineffective. The HIV-1 envelope protein gp120 binds to and signals through integrin α4β7 on T cells. We found that gp120 also bound to and signaled through α4β7 on naive B cells, which resulted in an abortive proliferative response. In primary B cells, signaling by gp120 through α4β7 resulted in increased expression of the immunosuppressive cytokine TGF-β1 and FcRL4, an inhibitory receptor expressed on B cells. Coculture of B cells with HIV-1-infected autologous CD4(+) T cells also increased the expression of FcRL4 by B cells. Our findings indicated that in addition to mediating chronic activation of the immune system, viral proteins contributed directly to HIV-1-associated B cell dysfunction. Our studies identify a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response.

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.

Human immunodeficiency virus (HIV) disease is associated with dysregulation and dysfunction involving all major lymphocyte populations, including B cells. Such perturbations occur early in the course of infection and are driven in large part by immune activation resulting from ongoing HIV replication leading to bystander effects on B cells. While most of the knowledge regarding immune cell abnormalities in HIV-infected individuals has been gained from studies conducted on the peripheral blood, it is clear that the virus is most active and most damaging in lymphoid tissues. Here, we discuss B-cell perturbations in HIV-infected individuals, focusing on the skewing of B-cell subsets that circulate in the peripheral blood and their counterparts that reside in lymphoid tissues. This review also highlights recent advances in evaluating HIV-specific B-cell responses both in the memory B-cell compartment, as well as in circulating antibody-secreting plasmablasts and the more differentiated plasma cells residing in tissues. Finally, we consider how knowledge gained by investigating B cells in HIV-infected individuals may help inform the development of an effective antibody-based HIV vaccine.

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.

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

Early administration of broadly neutralizing antibodies in a macaque SHIV infection model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. No effective vaccine has yet been developed against the human immunodeficiency virus type 1 (HIV-1), which is endemic in many areas of the world. Yoshiaki Nishimura et al. studied the effects of giving broadly neutralizing antibodies against HIV-1 to rhesus macaques shortly after beginning of exposure to low doses of the simian/human immunodeficiency virus (SHIV). This type of immunotherapy was associated with the persistence of low levels of the virus in the animals' blood, which led to the establishment of T-cell immunity and resulted in enhanced infection control. These findings could stimulate research into the mechanisms of HIV-1 control in infected humans. Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans1,2,3,4,5,6,7,8,9,10,11,12. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56–177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.

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.

Human immunodeficiency virus (HIV)-specific B-cell responses in infected individuals are maintained by active HIV replication. Suppression of viremia by antiretroviral therapy (ART) leads to quantitative and qualitative changes that remain unclear. Accordingly, B-cell responses were investigated in elite controllers (ECs), who maintain undetectable HIV levels without ART, and in individuals whose viremia was suppressed by ART. Despite a higher HIV burden in the ART group, compared with the EC group, frequencies of HIV-specific B cells were higher in the EC group, compared with those in the ART group. However, the initiation of ART in several ECs was associated with reduced frequencies of HIV-specific B cells, suggesting that responses are at least in part sustained by HIV replication. Furthermore, B-cell responses to tetanus toxin but not influenza hemagglutinin in the ART group were lower than those in the EC group. Thus, the superior HIV-specific humoral response in ECs versus ART-treated individuals is likely due to a more intact humoral immune response in ECs and/or distinct responses to residual HIV replication.

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.

Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1-infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell-associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load

Until recently, few potent and broadly neutralizing HIV-specific antibodies had been identified, but recent findings have inspired optimism that an effective HIV vaccine can finally be developed. Here we review these studies, which used state-of-the-art high-throughput techniques to collectively describe hundreds of new potent and broad HIV-neutralizing antibodies isolated from HIV-infected individuals.

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.

The programmed death (PD)-1 molecule and its ligands (PD-L1 and PD-L2), negative regulatory members of the B7 family, play an important role in peripheral tolerance. Previous studies have demonstrated that PD-1 is up-regulated on T cells following TCR-mediated activation; however, little is known regarding PD-1 and Ag-independent, cytokine-induced T cell activation. The common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21, which play an important role in peripheral T cell expansion and survival, were found to up-regulate PD-1 and, with the exception of IL-21, PD-L1 on purified T cells in vitro. This effect was most prominent on memory T cells. Furthermore, these cytokines induced, indirectly, the expression of PD-L1 and PD-L2 on monocytes/macrophages in PBMC. The in vivo correlate of these observations was confirmed on PBMC isolated from HIV-infected individuals receiving IL-2 immunotherapy. Exposure of γc cytokine pretreated T cells to PD-1 ligand-IgG had no effect on STAT5 activation, T cell proliferation, or survival driven by γc cytokines. However, PD-1 ligand-IgG dramatically inhibited anti-CD3/CD28-driven proliferation and Lck activation. Furthermore, following restimulation with anti-CD3/CD28, cytokine secretion by both γc cytokine and anti-CD3/CD28 pretreated T cells was suppressed. These data suggest that γc cytokine-induced PD-1 does not interfere with cytokine-driven peripheral T cell expansion/survival, but may act to suppress certain effector functions of cytokine-stimulated cells upon TCR engagement, thereby minimizing immune-mediated damage to the host.

Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20(hi)/CD27(lo)/CD21(lo)) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20(hi)/CD27(-)/CD21(lo)) when compared with B cells with a classical memory (CD27(+)) or naive (CD27(-)/CD21(hi)) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.

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.

Current efforts to prevent human immunodeficiency virus (HIV) disease, which largely focus on altering human behavior, have had some notable successes yet have failed to halt the spread of the acquired immunodeficiency syndrome pandemic. A greater understanding of the pathogenesis of HIV disease is providing us with the scientific rationale for additional approaches to prevention. Some of the approaches discussed in this article are available now. For example, we have the means to screen for and treat other sexually transmitted diseases that increase vulnerability to HIV, adult male circumcision is readily available in most properly equipped hospitals, and antiretroviral agents that decrease the viral load help prevent transmission from pregnant women to their infants. Other approaches discussed are under investigation. For instance, numerous topical microbicides are in various stages of development, incremental progress is being made toward creation of an HIV vaccine designed to prevent HIV transmission or slow the course of disease in people who become infected, and studies are under way to evaluate the risks and benefits of prophylactic antiretroviral therapy in individuals at high risk for HIV disease.

Follicular dendritic cells (FDC) represent a major extracellular reservoir for HIV. A better understanding of the mechanisms of virion attachment to FDC may offer new avenues for reducing viral burdens in infected individuals. We used a murine model to investigate the establishment of extracellular HIV reservoirs in lymph nodes (LN). Consistent with findings in human tissues, CD21 was required for trapping of HIV to LN cells, as evidenced by significantly reduced virion binding when mice were pretreated with a C3 ligand-blocking anti-CD21 mAb and absence of virion trapping in CD21 knockout mice. Also consistent with findings in human tissues, the majority of HIV virions were associated with the FDC-enriched fraction of LN cell preparations. Somewhat surprisingly, HIV-specific Abs were not essential for HIV binding to LN cells, indicating that seeding of the FDC reservoir may begin shortly after infection and before the development of HIV-specific Abs. Finally, the virion-displacing potential for anti-CD21 mAbs was investigated. Treatment of mice with anti-CD21 mAbs several days after injection of HIV significantly reduced HIV bound to LN cells. Our findings demonstrate a critical role for CD21 in HIV trapping by LN cells and suggest a new therapeutic avenue for reducing HIV reservoirs.

Classic preventive vaccines are designed to mimic the effects of natural exposure to microbes. They provide a high level of long-lasting protection against infection in the vast majority of recipients and serve as freestanding preventive measures. Although a classic preventive vaccine remains the ultimate goal of efforts to develop a vaccine for protection against the human immunodeficiency virus (HIV), the enormous genetic diversity and other unique features of the HIV envelope protein have thus far thwarted attempts to identify an effective candidate. However, we have learned from studies of HIV pathogenesis in humans and from animal models that a vaccine that induces strong T-cell–mediated immune responses in the absence of broadly neutralizing antibodies may prove beneficial even if infection is not completely prevented. Vaccine-induced T-cell responses may blunt initial viremia and prevent the early and massive destruction of memory CD4+ T cells that help control infection and prolong disease-free survival. Furthermore, secondary transmission may also be reduced if the vaccine helps to control viral replication; efficiency of transmission is directly related to plasma virus levels. T-cell vaccines represent uncharted territory, and their use may have outcomes that challenge researchers and regulators alike. If proven successful, a disease-modifying HIV vaccine would also present new challenges for the entire public health community, since it would not be a stand-alone preventive measure, as are most classic preventive vaccines. Instead, it would need to be delivered in the context of a comprehensive HIV-prevention program. OB S T AC L E S T O VAC C I NE DE V E L OPM E N T The development of more than two dozen antiretroviral therapies to combat HIV infection has resulted in a dramatic decrease in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS) in developed countries and, increasingly, in low- and middle-income countries as these therapies become more widely available. Despite ongoing prevention efforts, however, HIV continues to spread unabated in many parts of the world, with an estimated 14,000 new infections occurring daily. A safe and effective HIV vaccine would be an enormously valuable tool in the campaign to stop the spread of HIV. Most viruses against which successful vaccines have been developed undergo some level of initial replication and dispersal from the portal of entry before the virus reaches its target organ and triggers pathogenic sequelae. During this period, the virus remains vulnerable to eradication by the immune system. When prior immunization or exposure to a virus has elicited virus-specific immunologic memory, the increased speed and intensity of the immune response can prevent or mitigate disease. The nature of the interaction between HIV and the immune system is complex, and the relevance of different immune responses to the control of infection is only partially understood (Fig. 1). The primary stage of HIV infection begins with a burst