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The rebound-competent viral reservoir, composed of a virus that is able to persist during antiretroviral therapy (ART) and mediate reactivation of systemic viral replication and rebound viremia after ART interruption (ATI), remains the biggest obstacle to treating HIV infection. A better understanding of the cellular and tissue origins and the dynamics of viral populations that initiate rebound upon ATI could help develop therapeutic strategies for reducing the rebound-competent viral reservoir. In this study, barcoded simian immunodeficiency virus (SIV), SIVmac239M, was used to infect rhesus macaques to enable monitoring of viral barcode clonotypes contributing to virus detectable in plasma after ATI. Blood and tissues from secondary lymphoid organs (spleen, mesenteric lymph nodes, and inguinal lymph nodes) and from the colon, ileum, lung, liver, and brain were analyzed using viral barcode sequencing, intact proviral DNA assay, single-cell RNA sequencing, and combined CODEX and RNAscope in situ hybridization. Four of seven animals had viral barcodes detectable by deep sequencing of plasma at necropsy, although plasma viral RNA remained below 22 copies per milliliter. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. CD4+ T cells were the main cell type harboring viral RNA after ATI. Furthermore, T cell zones in lymphoid tissues showed higher viral RNA abundance than B cell zones for most animals. These findings are consistent with lymphoid tissues contributing to the virus present in plasma early after ATI. Editor's summary: A major hurdle to treating HIV is the continued presence of the rebound-competent viral reservoir, which persists during antiretroviral therapy (ART) and serves as a source of viremia during ART interruption (ATI). Here, Solis-Leal et al. infected rhesus macaques with a barcoded strain of simian immunodeficiency virus, SIVmac239M, that enabled tracking of viral clonotypes over time and between tissues. The macaques underwent two separate ATIs, and the authors compared barcodes present in the blood and tissues 1 week after ATI. The authors found that the re-emerged viral clonotypes in plasma at ATI-2 mainly overlapped with those found in the secondary lymphoid tissues such as the spleen and lymph nodes; they also found that CD4+ T cells harbored the most viral RNA after ATI. These data suggest that secondary lymphoid organs are likely the primary viral reservoir driving rebound early after ATI. —Courtney Malo [ABSTRACT FROM AUTHOR]

Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 env from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control. ARTsy antibodies: Post-treatment controllers (PTCs) are able to durably suppress human immunodeficiency virus (HIV)-1 after stopping antitretroviral therapy (ART). However, the features that distinguish PTCs from non-controllers (NC) remain unclear. Here, Esmaeilzadeh et al. evaluated plasma samples from six PTCs and six NCs who started ART early after infection, measuring viral load, viral diversity, and HIV-1 neutralizing antibody titers. The authors found that autologous neutralizing antibodies matured during antiretroviral therapy and was an important contributor to viral suppression after ART discontinuation. PTCs could be distinguished from NCs by a stronger neutralizing antibody response and a less diverse proviral reservoir. These features may be used to identify PTCs, although the authors highlight the need to look at a more diverse pool of individuals living with HIV-1. —CM [ABSTRACT FROM AUTHOR]

In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4+ T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti–PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4+ T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4+ T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti–PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti–PD-1 with other interventions to reduce the HIV reservoir. PD-1 blockade for HIV: Strategies to target and reverse the latent HIV reservoir are required to cure HIV. Because CD4+ T cells expressing programmed cell death protein 1 (PD-1) are preferentially infected with HIV in an individual on antiretroviral therapy, PD-1 is an attractive target to manipulate the latent reservoir. To this end, Uldrick et al. measured the impact of anti–PD-1 treatment with pembrolizumab on the HIV reservoir in 32 individuals living with HIV on suppressive antiretroviral therapy and diagnosed with cancer. They observed evidence of increased unspliced HIV RNA and of the unspliced RNA:DNA ratio, consistent with anti–PD-1 treatment having the potential to reverse HIV latency. Further studies are needed to evaluate the dose and frequency of anti–PD-1 treatment required for latency reversal. [ABSTRACT FROM AUTHOR]

A TLR7 agonist for HIV control: Toll-like receptor 7 (TLR7) agonists, combined with other therapies, can help to control immunodeficiency viruses in nonhuman primates. SenGupta et al. evaluated the safety and efficacy of vesatolimod, an oral TLR7 agonist, in people with HIV who had exhibited partial control of their virus—so-called "controllers"—before receiving antiretroviral therapy (ART). Compared to placebo, vesatolimod was associated with an increase in interferon signaling and NK cell and T cell activation and a decay in the frequency of cells harboring intact HIV genomes. Vesatolimod also induced a modest increase in the time to virus rebound after ART was interrupted. Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1–infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound was analyzed using the Kaplan-Meier method. Vesatolimod was associated with induction of immune cell activation, decreases in intact proviral DNA during ART, and a modest increase in time to rebound after ART was interrupted. The delayed viral rebound was predicted by the lower intact proviral DNA at the end of vesatolimod treatment (13 days after the final dose). Inferred pathway analysis suggested increased dendritic cell and natural killer cell cross-talk and an increase in cytotoxicity potential after vesatolimod dosing. Larger clinical studies will be necessary to assess the efficacy of vesatolimod-based combination therapies aimed at long-term control of HIV infection. [ABSTRACT FROM AUTHOR]

Putting pressure on HIV: Type 1 interferons provide early host immune defense against viruses, including HIV-1, by promoting expression of proteins that have direct or indirect antiviral activity. It remains unclear how viruses that persist long term, such as HIV-1, escape type 1 interferon–mediated pressure. Gondim et al. characterize interferon resistance in HIV-1 isolates acquired from HIV-1–infected individuals over several years. The authors found that HIV-1 isolates acquired at the time of initial infection or during interruption of antiretroviral therapy were the most resistant to type 1 interferons. These findings underpin the importance of type 1 interferons in controlling HIV-1 infection in the host. Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4+ T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC50) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant. [ABSTRACT FROM AUTHOR]

PrEPping to prevent HIV: Clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) can prevent HIV infection in high-risk populations. Geldsetzer et al. conducted a randomized study of health care facilities in Eswatini to see whether promoting PrEP could increase uptake among the general population at high risk of acquiring HIV. They found that the promotion package resulted in a small increase in PrEP uptake, but only one third of at-risk adults, mostly women, agreed to participate in PrEP. Crucially, interviews with study participants and health care workers revealed that PrEP promotion activities needed to be expanded beyond health care facilities into community settings to raise awareness, particularly among men. Clinical trials have shown that antiretroviral drugs used as pre-exposure prophylaxis (PrEP) are highly effective for preventing HIV acquisition. PrEP efforts, including in sub-Saharan Africa, have almost exclusively focused on certain priority groups, particularly female sex workers, men having sex with men, pregnant women, serodiscordant couples, and young women. As part of a PrEP demonstration project involving the general population at six primary health care facilities in Eswatini (formerly Swaziland), we conducted a randomized trial of a health care facility–based PrEP promotion package designed to increase PrEP uptake. Over the 18-month study duration, 33.6% (517 of 1538) of adults identified by health care workers as being at risk of acquiring HIV took up PrEP, and 30.0% of these individuals attended all scheduled appointments during the first 6 months after initiation of PrEP. The PrEP promotion package was associated with a 55% (95% confidence interval, 15 to 110%; P = 0.036) relative increase in the number of individuals taking up PrEP, with an absolute increase of 2.2 individuals per month per health care facility. When asked how PrEP uptake could be improved in 217 accompanying in-depth qualitative interviews, interviewees recommended an expansion of PrEP promotion activities beyond health care facilities to communities. Although a health care facility–based promotion package improved PrEP uptake, both uptake and retention remained low. Expanding promotion activities to the community is needed to achieve greater PrEP coverage among adults at risk of HIV infection in Eswatini and similar settings. [ABSTRACT FROM AUTHOR]

Making HIV its own worst enemy: Resistance to existing antivirals drives the need for identifying new ways to target HIV. Wang et al. screened a library of peptides from the HIV envelope protein to find ones that could inhibit the virus. One peptide, F9170, targeted HIV gp41 and was effective against free virions or HIV-infected cells. This peptide did not seem to be toxic or immunogenic in mice and is small enough to penetrate tissues that harbor HIV reservoirs. Simian-HIV–infected macaques treated with a short course of F9170 experienced a substantial drop in viral loads. Although further testing and development are needed, it could one day be part of a new treatment regimen for HIV. HIV-associated morbidity and mortality have markedly declined because of combinational antiretroviral therapy, but HIV readily mutates to develop drug resistance. Developing antivirals against previously undefined targets is essential to treat existing drug-resistant HIV strains. Some peptides derived from HIV-1 envelope glycoprotein (Env, gp120-gp41) have been shown to be effective in inhibiting HIV-1 infection. Therefore, we screened a peptide library from HIV-1 Env and identified a peptide from the cytoplasmic region, designated F9170, able to effectively inactivate HIV-1 virions and induce necrosis of HIV-1–infected cells, and reactivated latently infected cells. F9170 specifically targeted the conserved cytoplasmic tail of HIV-1 Env and effectively disrupted the integrity of the viral membrane. Short-term monoadministration of F9170 controlled viral loads to below the limit of detection in chronically SHIV-infected macaques. F9170 can enter the brain and lymph nodes, anatomic reservoirs for HIV latency. Therefore, F9170 shows promise as a drug candidate for HIV treatment. [ABSTRACT FROM AUTHOR]

Sorting out HIV: The latent reservoir of HIV-1–infected cells that persist in, otherwise, virally suppressed individuals constitutes the major barrier to cure. Liu et al. developed a method called HIV-1 SortSeq to identify rare HIV-infected CD4+ T cells from individuals on antiretroviral therapies upon latency reversal ex vivo. Analysis of the isolated single cells showed that the 5′ long terminal repeat of HIV-1 was capable of driving the transcription of host genes downstream of the integration site, which may contribute to HIV persistence. Understanding HIV-1–host interactions can identify the cellular environment supporting HIV-1 reactivation and mechanisms of clonal expansion. We developed HIV-1 SortSeq to isolate rare HIV-1–infected cells from virally suppressed, HIV-1–infected individuals upon early latency reversal. Single-cell transcriptome analysis of HIV-1 SortSeq+ cells revealed enrichment of nonsense-mediated RNA decay and viral transcription pathways. HIV-1 SortSeq+ cells up-regulated cellular factors that can support HIV-1 transcription (IMPDH1 and JAK1) or promote cellular survival (IL2 and IKBKB). HIV-1–host RNA landscape analysis at the integration site revealed that HIV-1 drives high aberrant host gene transcription downstream, but not upstream, of the integration site through HIV-1–to–host aberrant splicing, in which HIV-1 RNA splices into the host RNA and aberrantly drives host RNA transcription. HIV-1–induced aberrant transcription was driven by the HIV-1 promoter as shown by CRISPR-dCas9–mediated HIV-1–specific activation and could be suppressed by CRISPR-dCas9–mediated inhibition of HIV-1 5′ long terminal repeat. Overall, we identified cellular factors supporting HIV-1 reactivation and HIV-1–driven aberrant host gene transcription as potential therapeutic targets to disrupt HIV-1 persistence. [ABSTRACT FROM AUTHOR]

Hidden in plain sight: Human platelets carry out several immune functions as well as hemostasis and interact with infectious pathogens including HIV in vitro. Real et al. now report that platelets from HIV-infected individuals can harbor replication-competent HIV, despite successful viral suppression by antiretroviral drug therapy (ART). Moreover, in their study, >80% of virally suppressed HIV-infected individuals with platelets containing HIV showed poor restoration of immune status even 1 year after ART treatment initiation. Platelets carrying HIV may provide an alternative pathway for HIV dissemination in HIV-infected individuals on ART with viral suppression and poor CD4+ T cell recovery. In addition to hemostasis, human platelets have several immune functions and interact with infectious pathogens including HIV in vitro. Here, we report that platelets from HIV-infected individuals on combined antiretroviral drug therapy (ART) with low blood CD4+ T cell counts (<350 cells/μl) contained replication-competent HIV despite viral suppression. In vitro, human platelets harboring HIV propagated the virus to macrophages, a process that could be prevented with the biologic abciximab, an anti–integrin αIIb/β3 Fab. Furthermore, in our cohort, 88% of HIV-infected individuals on ART with viral suppression and with platelets containing HIV were poor immunological responders with CD4+ T cell counts remaining below <350 cells/μl for more than one year. Our study suggests that platelets may be transient carriers of HIV and may provide an alternative pathway for HIV dissemination in HIV-infected individuals on ART with viral suppression and poor CD4+ T cell recovery. [ABSTRACT FROM AUTHOR]

Breaching the latent HIV reservoir: The main barrier to curing HIV-1 infection is a latent reservoir of the virus in resting CD4+ T cells, which allows the virus to persist in a form that is not detected by the immune system or affected by antiretroviral drugs. One cure strategy involves inducing viral gene expression so that latently infected T cells can be eliminated. It has been suggested that latent HIV-1 might be enriched in specific subpopulations of CD4+ T cells, which would allow more specific targeting of latency-reversing drugs. In a new study, Kwon et al. now report that surprisingly there was no preferential enrichment or differences in viral gene expression inducibility among naïve CD4+ T cells and three different subsets of memory CD4+ T cells from 10 HIV-infected individuals on antiretroviral therapy. This finding complicates targeted cure strategies based on CD4+ T cell subsets. The latent reservoir of HIV-1 in resting CD4+ T cells is a major barrier to cure. It is unclear whether the latent reservoir resides principally in particular subsets of CD4+ T cells, a finding that would have implications for understanding its stability and developing curative therapies. Recent work has shown that proliferation of HIV-1–infected CD4+ T cells is a major factor in the generation and persistence of the latent reservoir and that latently infected T cells that have clonally expanded in vivo can proliferate in vitro without producing virions. In certain CD4+ memory T cell subsets, the provirus may be in a deeper state of latency, allowing the cell to proliferate without producing viral proteins, thus permitting escape from immune clearance. To evaluate this possibility, we used a multiple stimulation viral outgrowth assay to culture resting naïve, central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells from 10 HIV-1–infected individuals on antiretroviral therapy. On average, only 1.7% of intact proviruses across all T cell subsets were induced to transcribe viral genes and release replication-competent virus after stimulation of the cells. We found no consistent enrichment of intact or inducible proviruses in any T cell subset. Furthermore, we observed notable plasticity among the canonical memory T cell subsets after activation in vitro and saw substantial person-to-person variability in the inducibility of infectious virus release. This finding complicates the vision for a targeted approach for HIV-1 cure based on T cell memory subsets. [ABSTRACT FROM AUTHOR]

Au revoir HIV reservoir?: Curing HIV requires eliminating the latent viral reservoir. To better understand how this reservoir is formed, Abrahams et al. examined longitudinal samples from nine South African women with HIV. HIV was grown from resting CD4+ T cells isolated after several years of antiretroviral therapy (ART) and compared to viral sequences from longitudinal samples collected before ART. They found that in most subjects, reservoir viral sequences were related to viruses present at the time of ART initiation. These results suggest that the majority of the latent reservoir is seeded in response to therapy and likely is not continually formed prior to ART. HIV treatment and cure efforts could potentially exploit this information to limit the size of the reservoir when treatment is initiated. Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation. [ABSTRACT FROM AUTHOR]

The author reflects on challenges in replicating research studies. He comments on a paper published in the journal, "Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy" by Byrareddy and others in which the study's coauthor used an SIV strain with a stop codon in the Nef gene but failed to effectively communicate that fact. He mentions how this caused problems with replication of the research study.

Driving a new HIV therapy forward: CAR T cells, which are now associated with cancer therapy, were previously investigated as a treatment for HIV almost 30 years ago. Now wielding new technology and biological knowledge, Anthony-Gonda et al. report a series of multispecific anti-HIV CARs. These CARs target different portions of the HIV envelope protein and were able to eliminate diverse strains of HIV in vitro, even those that are resistant to potent broadly neutralizing antibodies. The CAR T cells are resistant to HIV infection and were able to control HIV in a humanized mouse model. The persistent surveillance capabilities of CAR T cells suggest that this therapy may one day be able to eradicate HIV in an infected person. Adoptive immunotherapy using chimeric antigen receptor–modified T cells (CAR-T) has made substantial contributions to the treatment of certain B cell malignancies. Such treatment modalities could potentially obviate the need for long-term antiretroviral drug therapy in HIV/AIDS. Here, we report the development of HIV-1–based lentiviral vectors that encode CARs targeting multiple highly conserved sites on the HIV-1 envelope glycoprotein using a two-molecule CAR architecture, termed duoCAR. We show that transduction with lentiviral vectors encoding multispecific anti-HIV duoCARs confer primary T cells with the capacity to potently reduce cellular HIV infection by up to 99% in vitro and >97% in vivo. T cells are the targets of HIV infection, but the transduced T cells are protected from genetically diverse HIV-1 strains. The CAR-T cells also potently eliminated PBMCs infected with broadly neutralizing antibody-resistant HIV strains, including VRC01/3BNC117-resistant HIV-1. Furthermore, multispecific anti-HIV duoCAR-T cells demonstrated long-term control of HIV infection in vivo and prevented the loss of CD4+ T cells during HIV infection using a humanized NSG mouse model of intrasplenic HIV infection. These data suggest that multispecific anti-HIV duoCAR-T cells could be an effective approach for the treatment of patients with HIV-1 infection. [ABSTRACT FROM AUTHOR]

Hidden in Plain Sight: Insufficient exposure of tissues harboring residual HIV, including the gut, to antiretroviral drugs may contribute to HIV persistence. Thompson et al. now apply a mass spectrometry–based imaging technique to visualize the distribution of six antiretroviral drugs in gut tissue sections from two animal species (mice and macaques) and HIV-infected patients. The authors found that drug distribution was uneven throughout the gut tissue. They also found that a major proportion of gut T cells, which are targeted by HIV, did not colocalize with an antiretroviral drug. In addition, viral RNA could still be detected during drug treatment, particularly in areas of low antiretroviral drug concentrations, potentially contributing to ongoing viral replication. HIV replication within tissues may increase in response to a reduced exposure to antiretroviral drugs. Traditional approaches to measuring drug concentrations in tissues are unable to characterize a heterogeneous drug distribution. Here, we used mass spectrometry imaging (MSI) to visualize the distribution of six HIV antiretroviral drugs in gut tissue sections from three species (two strains of humanized mice, macaques, and humans). We measured drug concentrations in proximity to CD3+ T cells that are targeted by HIV, as well as expression of HIV or SHIV RNA and expression of the MDR1 drug efflux transporter in gut tissue from HIV-infected humanized mice, SHIV-infected macaques, and HIV-infected humans treated with combination antiretroviral drug therapy. Serial 10-μm sections of snap-frozen ileal and rectal tissue were analyzed by MSI for CD3+ T cells and MDR1 efflux transporter expression by immunofluorescence and immunohistochemistry, respectively. The tissue slices were analyzed for HIV/SHIV RNA expression by in situ hybridization and for antiretroviral drug concentrations by liquid chromatography–mass spectrometry. The gastrointestinal tissue distribution of the six drugs was heterogeneous. Fifty percent to 60% of CD3+ T cells did not colocalize with detectable drug concentrations in the gut tissue. In all three species, up to 90% of HIV/SHIV RNA was found to be expressed in gut tissue with no exposure to drug. These data suggest that there may be gut regions with little to no exposure to antiretroviral drugs, which may result in low-level HIV replication contributing to HIV persistence. [ABSTRACT FROM AUTHOR]

SIV-infected rhesus macaques on antiretroviral therapy experienced a reduction in the SIV reservoir after treatment with TLR7 agonists. Emptying the reservoir: Antiretroviral therapy can halt HIV-1 replication but cannot clear the hidden reservoirs of latent virus. In new work, Lim et al. treated SIV-infected rhesus macaques on antiretroviral therapy with up to 19 doses of the Toll-like receptor 7 agonists GS-986 or GS-9620. By the third dose, all macaques experienced transient SIV plasma viremia within 48 hours after dosing. Dosing was also associated with activation of lymphocytes (T, NK, and B cells) and reductions in SIV DNA in cells from the peripheral blood, lymph nodes, and gastrointestinal tract. When antiretroviral therapy ceased, 2 of 13 treated macaques did not show rebound of virus and remained virus-free and disease-free for more than 2 years. Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist–induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8+ T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naïve recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV-infected rhesus macaques. [ABSTRACT FROM AUTHOR]

The article reports on a therapeutic vaccine regimen in HIV-infected individuals in whom antiretroviral therapy was initiated during the early stage of HIV infection. The randomized, placebo-controlled trial was conducted to determine whether the vaccine was safe and could induce an immune response.

Information about several papers discussed at the 20th International AIDS Conference in Melbourne, Australia from July 20-25, 2014 on HIV-positive people clearing the HIV virus from their systems is presented. Topics include HIV patient Timothy Ray Brown, antiretroviral (ARV) drug cocktails, and measuring an intervention's effectiveness at depleting HIV virus reservoirs. The symposium featured immunologists John Zaunders and Daniel Kuritzkes, and HIV cure researcher Sharon Lewin.