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Summary Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4+ T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (~9 kb) HIV-1 proviral genomes and determines potential replication-competency through genetic characterization. FLIPS provides a genome-scale perspective which addresses the limitations of other methods that also genetically characterize the latent reservoir. Using FLIPS, we identified 5% proviruses as intact and potentially replication-competent. Intact proviruses were unequally distributed between T cell subsets, with effector memory cells containing the largest proportion of genetically intact HIV-1 proviruses. We identified multiple identical intact proviruses suggesting a role for cellular proliferation in the maintenance of the latent HIV-1 reservoir.

Despite the presence of reduced drug susceptibility, antiretroviral-drug therapy can provide immunologic and virologic benefit. This benefit reflects continued antiviral-drug activity and the maintenance of a viral population with a reduced replicative capacity.

HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.

BACKGROUNDUniversal antiretroviral therapy (ART) with annual population testing and a multidisease, patient-centered strategy could reduce new human immunodeficiency virus (HIV) infections and improve community health. METHODSWe randomly assigned 32 rural communities in Uganda and Kenya to baseline HIV and multidisease testing and national guideline-restricted ART (control group) or to baseline testing plus annual testing, eligibility for universal ART, and patient-centered care (intervention group). The primary end point was the cumulative incidence of HIV infection at 3 years. Secondary end points included viral suppression, death, tuberculosis, hypertension control, and the change in the annual incidence of HIV infection (which was evaluated in the intervention group only). RESULTSA total of 150,395 persons were included in the analyses. Population-level viral suppression among 15,399 HIV-infected persons was 42% at baseline and was higher in the intervention group than in the control group at 3 years (79% vs. 68%; relative prevalence, 1.15; 95% confidence interval [CI], 1.11 to 1.20). The annual incidence of HIV infection in the intervention group decreased by 32% over 3 years (from 0.43 to 0.31 cases per 100 personyears; relative rate, 0.68; 95% CI, 0.56 to 0.84). However, the 3-year cumulative incidence (704 incident HIV infections) did not differ significantly between the intervention group and the control group (0.77% and 0.81%, respectively; relative risk, 0.95; 95% CI, 0.77 to 1.17). Among HIV-infected persons, the risk of death by year 3 was 3% in the intervention group and 4% in the control group (0.99 vs. 1.29 deaths per 100 person-years; relative risk, 0.77; 95% CI, 0.64 to 0.93). The risk of HIV-associated tuberculosis or death by year 3 among HIV-infected persons was 4% in the intervention group and 5% in the control group (1.19 vs. 1.50 events per 100 person-years; relative risk, 0.79; 95% CI, 0.67 to 0.94). At 3 years, 47% of adults with hypertension in the intervention group and 37% in the control group had hypertension control (relative prevalence, 1.26; 95% CI, 1.15 to 1.39). CONCLUSIONSUniversal HIV treatment did not result in a significantly lower incidence of HIV infection than standard care, probably owing to the availability of comprehensive baseline HIV testing and the rapid expansion of ART eligibility in the control group. (Funded by the National Institutes of Health and others; SEARCH ClinicalTrials.gov number, NCT01864603.

Background Despite large investments in HIV testing, only 45% of HIV-infected persons in sub-Saharan Africa are estimated to know their status. Optimal methods for maximizing population-level testing remain unknown. We sought to demonstrate the effectiveness at achieving population-wide testing coverage of a hybrid mobile HIV testing approach. Methods From 2013–2014, we enumerated 168,772 adult (≥15 years) residents of 32 communities in Uganda (N=20), and Kenya (N=12) using a door-to-door census. “Stable” residence was defined as living in community for ≥6 months over the past year. In each community we performed 2-week multi-disease community health campaigns (CHC) that included HIV testing, counseling, and referral to care if HIV-infected; CHC non-participants were approached for home-based testing (HBT) over 1–2 months. We determined population HIV testing coverage, and predictors of testing via HBT (vs. CHC) and non-testing. Findings HIV testing was achieved in 89% of stable adult residents (131,307/146,906). HIV prevalence was 9.6% (13,043/136,033 stable and non-stable adults); median CD4+ T-cell count was 514 cells/μL (IQR: 355–703). Among stable adults tested, 43% (56,106/131,307) reported no prior testing. Among HIV-infected adults, 38% (4,932/13,043) were unaware of their status. Among stable CHC attendees, 99.5% (104,635/105,170) accepted HIV testing. Of stable adults tested, 80% (104,635/131,307, range: 60–93%) tested via CHCs. In multivariable analyses of stable adults, predictors of non-testing included male gender (risk ratio [RR]: 1.52, 95% CI: 1.48–1.56), single marital status (RR: 1.70, 95% CI: 1.66–1.75), Kenyan residence (RR: 1.46, 95% CI: 1.41–1.50, vs. Ugandan), and out-of-community migration for ≥1 month in past year (RR: 1.60, 95% CI: 1.53–1.68). Testing was more common among farmers (RR: 0.73, 95% CI: 0.67–0.79) and adults with primary education (RR: 0.84, 95% CI: 0.80–0.89). Interpretation High HIV testing coverage was achieved in rural Ugandan and Kenyan communities using a hybrid, mobile approach of multi-disease CHCs followed by HBT. This approach allowed for flexibility at the community and individual level in reaching testing coverage goals. Men and mobile populations remain challenges for universal testing.

Background: Central nervous system (CNS) exposure to HIV is a universal facet of systemic infection. Because of its proximity to and shared barriers with the brain, cerebrospinal fluid (CSF) provides a useful window into and model of human CNS HIV infection.

clinicaltrials.gov Identifier: NCT01864683.