The spread of HIV between immune cells is greatly enhanced by cell-cell adhesions called virological synapses, although the underlying mechanisms have been unclear. With use of an infectious, fluorescent clone of HIV, we tracked the movement of Gag in live CD4 T cells and captured the direct translocation of HIV across the virological synapse. Quantitative, high-speed three-dimensional (3D) video microscopy revealed the rapid formation of micrometer-sized “buttons” containing oligomerized viral Gag protein. Electron microscopy showed that these buttons were packed with budding viral crescents. Viral transfer events were observed to form virus-laden internal compartments within target cells. Continuous time-lapse monitoring showed preferential infection through synapses. Thus, HIV dissemination may be enhanced by virological synapse-mediated cell adhesion coupled to viral endocytosis.

Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebocontrolled study, a single subcutaneous dose of rhIL-7 was well tolerated with biologic activity demonstrable at 3 g/kg and a maximum tolerated dose of 30 g/kg.

Importance Treatment of hepatitis C virus (HCV) infection in HIV-1 co-infected patients has been limited due to the use of interferon and drug interactions with antiretroviral therapies (ART). Objective To determine the rates of HCV eradication (sustained virologic response, SVR) and adverse events in HCV/HIV-1 co-infected patients receiving sofosbuvir and ribavirin treatment. Design Multicenter, open-label, non-randomized, uncontrolled phase 3 trial (PHOTON-1) conducted in the United States and Puerto Rico from August 2012 until November 2013 evaluating treatment with sofosbuvir and ribavirin. Setting Thirty-four academic, private practice, and community health centers with a median of 6 patients (range 1–17) enrolled at each site. Participants Patients with HCV genotypes 1, 2, or 3 and concurrent HIV-1 were eligible. Patients were required to be receiving antiretroviral treatment with an HIV-1 RNA <50 copies/mL and a CD4 T-cell count of >200 cells/mm3 or have untreated HIV-1infection with a CD4 T-cell count of >500 cells/mm3. In total, 223 participants (114 treatment-naïve participants with HCV genotype 1, 68 treatment-naïve participants with HCV genotype 2 or 3, and 41 peginterferon/ribavirin treatment-experienced participants with HCV genotype 2 or 3) were enrolled. Interventions Participants received sofosbuvir (400 mg) and weight-based ribavirin for 12 weeks (for treatment-naïve patients with HCV genotype 2 or 3) or for 24 weeks (for treatment-naïve patients with HCV genotype 1 or treatment-experienced patients with HCV genotype 2 or 3). Main Outcome and Measure The primary study outcome was proportion of patients with SVR (serum HCV <25 copies/mL) 12 weeks after cessation of HCV therapy (SVR12). Results Among treatment-naïve participants, SVR12 rates were 76% (95% confidence interval [CI], 67–84) for genotype 1 infection, 88% (95% CI, 70–98) for genotype 2 infection, and 67% (95% CI, 51–80) for genotype 3 infection. Among treatment-experienced participants, SVR12 was 92% (95% CI, 73–99) for genotype 2 infection and 94% (95% CI, 71–100) for genotype 3 infection. The most common adverse events were fatigue, insomnia, headache, and nausea. Seven patients (3%) discontinued HCV treatment due to adverse events. No adverse effect on HIV disease or its treatment was observed. Conclusions and Relevance In this open-label, nonrandomized, uncontrolled phase 3 study, HIV-1-infected patients coinfected with HCV genotype 1, 2, or 3 who received the oral, interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of sustained virologic response 12 weeks after cessation of therapy. Further studies of this oral regimen in diverse populations of coinfected patients are warranted. Trial Registration clinicaltrials.gov Identifier: NCT01667731

Background Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized. Methods Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4+, CD4+ naive and memory, CD4+ activation, CD8+, CD8+ activation, B, and natural killer cells among patients in different baseline CD4+ strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113. Results Patients in the lower baseline CD4+ strata did not achieve total CD4+ cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4+ cell count increases were similar. Ratios of CD4+ naive-memory cell counts and CD4+:CD8+ cell counts remained significantly reduced in patients with lower baseline CD4+ cell counts (≤350 cells/mm3). These immune imbalances were most notable for those initiating ART with a baseline CD4+ cell count ≤200 cells/mm3, even after adjustment for baseline plasma HIV RNA levels. Conclusions After nearly 3 years of ART, T cell subsets in patients with baseline CD4+ cell counts >350 cells/mm3 achieved or approached the reference range those of control individuals without HIV infection. In contrast, patients who began ART with ≤350 CD4+ cells/mm3 generally did not regain normal CD4+ naive-memory cell ratios. These results support current guidelines to start ART at a threshold of 350 cells/mm3 and suggest that there may be immunological benefits associated with initiating therapy at even higher CD4+ cell counts.

In this large randomized trial, younger age, female sex, higher naive/memory CD4 cell ratio, higher baseline VL, and VS were associated with greater CD4 cell increase, whereas persistent T-cell activation was associated with impaired CD4 cell recovery after ART initiation. Initial treatment assignment did not affect CD4 cell reconstitution.