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The functional properties of circulating CD8+ T cells have been associated with immune control of HIV. However, viral replication occurs predominantly in secondary lymphoid tissues, such as lymph nodes (LNs). We used an integrated single-cell approach to characterize effective HIV-specific CD8+ T cell responses in the LNs of elite controllers (ECs), defined as individuals who suppress viral replication in the absence of antiretroviral therapy (ART). Higher frequencies of total memory and follicle-homing HIV-specific CD8+ T cells were detected in the LNs of ECs compared with the LNs of chronic progressors (CPs) who were not receiving ART. Moreover, HIV-specific CD8+ T cells potently suppressed viral replication without demonstrable cytolytic activity in the LNs of ECs, which harbored substantially lower amounts of CD4+ T cell-associated HIV DNA and RNA compared with the LNs of CPs. Single-cell RNA sequencing analyses further revealed a distinct transcriptional signature among HIV-specific CD8+ T cells from the LNs of ECs, typified by the down-regulation of inhibitory receptors and cytolytic molecules and the up-regulation of multiple cytokines, predicted secreted factors, and components of the protein translation machinery. Collectively, these results provide a mechanistic framework to expedite the identification of novel antiviral factors, highlighting a potential role for the localized deployment of noncytolytic functions as a determinant of immune efficacy against HIV.

Actinic keratosis (AK) is a precancerous skin lesion that is common in HIV-positive patients. Without effective treatment, AKs can progress to squamous cell carcinoma. Ingenol mebutate, a PKC agonist, is a US Food and Drug Administration-approved (FDA-approved) topical treatment for AKs. It can induce reactivation of latent HIV transcription in CD4+ T cells both in vitro and ex vivo. Although PKC agonists are known to be potent inducers of HIV expression from latency, their effects in vivo are not known because of the concerns of toxicity. Therefore, we sought to determine the effects of topical ingenol mebutate gel on the HIV transcription profile in HIV-infected individuals with AKs, specifically in the setting of suppressive antiretroviral therapy (ART). We found that AKs cleared following topical application of ingenol mebutate and detected marginal changes in immune activation in the peripheral blood and in skin biopsies. An overall increase in the level of HIV transcription initiation, elongation, and complete transcription was detected only in skin biopsies after the treatment. Our data demonstrate that application of ingenol mebutate to AKs in ART-suppressed HIV-positive patients can effectively cure AKs as well as disrupt HIV latency in the skin tissue microenvironment in vivo without causing massive immune activation.

Therapeutic strategies that augment antiviral immunity and reduce the viral reservoir are critical to achieving durable remission of HIV. The coinhibitory receptor programmed death-1 (PD-1) regulates CD8+ T cell dysfunction during chronic HIV and SIV infections. We previously demonstrated that in vivo blockade of PD-1 during chronic SIV infection improves the function of antiviral CD8+ T cells and B cells. Here, we tested the immunological and virological effects of PD-1 blockade combined with antiretroviral therapy (ART) in rhesus macaques. Administration of anti-PD-1 antibody 10 days prior to ART initiation rapidly enhanced antiviral CD8+ T cell function and diminished IFN-stimulated genes. This resulted in faster viral suppression in plasma and better Th17 cell reconstitution in the rectal mucosa following ART initiation. PD-1 blockade during ART resulted in lower levels of cell-associated replication-competent virus. Following ART interruption, PD-1 antibody-treated animals showed markedly higher expansion of proliferating CXCR5+perforin+granzyme B+ effector CD8+ T cells and lower regulatory T cells that resulted in better control of viremia. Our results show that PD-1 blockade can be administered safely with ART to augment antiviral CD8+ T cell function and reduce the viral reservoir, leading to improved control of viral rebound after ART interruption.

BackgroundFibrosis in lymph nodes may limit CD4+ T-cell recovery, and lymph node and adipose tissue fibrosis may contribute to inflammation and comorbidities despite antiretroviral therapy (ART). We hypothesized that the angiotensin receptor blocker and peroxisome proliferator-activated receptor γ agonist telmisartan would decrease lymph node or adipose tissue fibrosis in treated human immunodeficiency virus type 1 (HIV) infection.MethodsIn this 48-week, randomized, controlled trial, adults continued HIV-suppressive ART and received telmisartan or no drug. Collagen I, fibronectin, and phosphorylated SMAD3 (pSMAD3) deposition in lymph nodes, as well as collagen I, collagen VI, and fibronectin deposition in adipose tissue, were quantified by immunohistochemical analysis at weeks 0 and 48. Two-sided rank sum and signed rank tests compared changes over 48 weeks.ResultsForty-four participants enrolled; 35 had paired adipose tissue specimens, and 29 had paired lymph node specimens. The median change overall in the percentage of the area throughout which collagen I was deposited was -2.6 percentage points (P = 0.08) in lymph node specimens and -1.3 percentage points (P = .001) in adipose tissue specimens, with no between-arm differences. In lymph node specimens, pSMAD3 deposition changed by -0.5 percentage points overall (P = .04), with no between-arm differences. Telmisartan attenuated increases in fibronectin deposition (P = .06). In adipose tissue, changes in collagen VI deposition (-1.0 percentage point; P = .001) and fibronectin deposition (-2.4 percentage points; P < .001) were observed, with no between-arm differences.ConclusionsIn adults with treated HIV infection, lymph node and adipose tissue fibrosis decreased with continued ART alone, with no additional fibrosis reduction with telmisartan therapy.

In the quest for a functional cure or the eradication of HIV infection, it is necessary to know the sizes of the reservoirs from which infection rebounds after treatment interruption. Thus, we quantified SIV and HIV tissue burdens in tissues of infected nonhuman primates and lymphoid tissue (LT) biopsies from infected humans. Before antiretroviral therapy (ART), LTs contained >98% of the SIV RNA+ and DNA+ cells. With ART, the numbers of virus (v) RNA+ cells substantially decreased but remained detectable, and their persistence was associated with relatively lower drug concentrations in LT than in peripheral blood. Prolonged ART also decreased the levels of SIV- and HIV-DNA+ cells, but the estimated size of the residual tissue burden of 108 vDNA+ cells potentially containing replication-competent proviruses, along with evidence of continuing virus production in LT despite ART, indicated two important sources for rebound following treatment interruption. The large sizes of these tissue reservoirs underscore challenges in developing 'HIV cure' strategies targeting multiple sources of virus production.

In HIV-1-infected patients, increased numbers of circulating CD8+ T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell activation and expansion in untreated HIV-1-infected patients. Compared with healthy controls, untreated HIV-1-infected patients have an increased population of proliferating, granzyme B+, CD8+ T cells in circulation. Vβ expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme B+ phenotype in CD8+ T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1-infected patients correlated with circulating CD8+ T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of CD8+ T cells, which predicts disease progression in untreated HIV-1-infected patients and suggests that elevated IL-15 may also drive CD8+ T cell expansion that is linked to increased morbidity and mortality in treated patients.

ObjectiveMicrobial translocation and innate immune action characterize HIV infection. Continued gut mucosal dysfunction during treatment and its relationship to CD4 T-cell recovery has not been well described.DesignA cross-sectional study was performed of antiretroviral therapy (ART)-suppressed (immunologic responders with CD4 > 500 cells/μl and immunologic nonresponders with CD4

ObjectiveMicrobial translocation and innate immune action characterize HIV infection. Continued gut mucosal dysfunction during treatment and its relationship to CD4 T-cell recovery has not been well described.DesignA cross-sectional study was performed of antiretroviral therapy (ART)-suppressed (immunologic responders with CD4 > 500 cells/μl and immunologic nonresponders with CD4