Dendritic cells (DC) have an instrumental role in the activation and function of both innate and adaptive immune responses. In humans, at least two distinct DC subsets have been characterized based on phenotypic markers: the myeloid DC (MDC) and the plasmacytoid DC (PDC). Both subsets are critical producers of cytokines (IL-12 for MDC and type I/II IFNs for PDC) and are functionally different. We show in this study that HIV+ individuals have a significant decrease in the number of the Lin−HLA-DR+CD123+ and BDCA-2+ PDC compared with uninfected donors (p = 0.0001). HIV+ individuals also have a sustained impairment in viral-induced IFN-α production (p < 0.0001). The decrease of the PDC subsets did not correlate with CD4 count or viral load and was not reversed in subjects under virally suppressive treatment, suggesting an irreversible change after infection. By contrast, the absolute number and median frequency of MDC in HIV-infected individuals were similar to those observed in uninfected controls, while a significant decrease was present in subjects with >5000 HIV-1 copies/ml. The inverse association with viral load of the MDC number, but not of IFN-α secretion or the number of PDC, suggests a role for MDC in viral control. Our data suggest that DC subsets are differentially reconstituted during the immune recovery associated with antiviral therapy. The persistent impairment of certain DC subsets may result in a sustained defect in DC-mediated innate immune functions despite an effective treatment regimen.

Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose.Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24.Results. Mean change in HIV-1 RNA at day 8 was −1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily.Conclusions. DTG 50 mg BID–based therapy was effective in this highly treatment-experienced population with INI-resistant virus.Clinical Trials Registration.  (NCT01328041) and (112574).

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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

NCT00594880.

BackgroundRetention in HIV care improves survival and reduces the risk of HIV transmission to others. Multiple quantitative studies have described demographic and clinical characteristics associated with retention in HIV care. However, qualitative studies are needed to better understand barriers and facilitators.MethodsSemi-structured interviews were conducted with 51 HIV-infected individuals, 25 who were retained in care and 26 not retained in care, from 3 urban clinics. Interview data were analyzed for themes using a modified grounded theory approach. Identified themes were compared between the two groups of interest: patients retained in care and those not retained in care.ResultsOverall, participants identified 12 barriers and 5 facilitators to retention in HIV care. On average, retained individuals provided 3 barriers, while persons not retained in care provided 5 barriers. Both groups commonly discussed depression/mental illness, feeling sick, and competing life activities as barriers. In addition, individuals not retained in care commonly reported expensive and unreliable transportation, stigma, and insufficient insurance as barriers. On average, participants in both groups referenced 2 facilitators, including the presence of social support, patient-friendly clinic services (transportation, co-location of services, scheduling/reminders), and positive relationships with providers and clinic staff.ConclusionsIn our study, patients not retained in care faced more barriers, particularly social and structural barriers, than those retained in care. Developing care models where social and financial barriers are addressed, mental health and substance abuse treatment is integrated, and patient-friendly services are offered is important to keeping HIV-infected individuals engaged in care.

The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to m ark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total H IV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA-positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART.

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