HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. The depletion of antigen-specific CD4 T cells during ...HIV infection is therefore believed to impede the development of protective B cell immunity. Although several different HIV-related B cell dysfunctions have been described, the role of CD4 T follicular helper (TFH) cells in HIV infection remains unknown. Here, we assessed HIV-specific TFH responses in the lymph nodes of treatment-naive and antiretroviral-treated HIV-infected individuals. Strikingly, both the bulk TFH and HIV-specific TFH cell populations were significantly expanded in chronic HIV infection and were highly associated with viremia. In particular, GAG-specific TFH cells were detected at significantly higher levels in the lymph nodes compared with those of GP120-specific TFH cells and showed preferential secretion of the helper cytokine IL-21. In addition, TFH cell expansion was associated with an increase of germinal center B cells and plasma cells as well as IgG1 hypersecretion. Thus, our study suggests that high levels of HIV viremia drive the expansion of TFH cells, which in turn leads to perturbations of B cell differentiation, resulting in dysregulated antibody production.
HIV-HCV co-infection is associated with accelerated progression to hepatic fibrosis, cirrhosis and hepatocellular carcinoma than HCV mono-infection. The contribution of innate immunity during HIV-HCV ...co-infection has been a relatively under-investigated area. Natural killer (NK) cells are pivotal sentinels of innate immunity against viruses and tumour cells. In this study we evaluated the effect of HIV-HCV co-infection on peripheral blood NK cell subsets with emphasis on the phenotype of CD56.sup.bright NK cells. Sixty patients were included in the study; HIV mono-infected (n = 12), HCV mono-infected (n = 15), HCV-HIV co-infected (n = 21) and healthy controls (n = 16). PBMCs were isolated and immunophenotyping of NK cells was performed by flowcytometry. We observed an expansion of CD56.sup.bright NK cell subset in HIV-HCV co-infection as compared to healthy controls and HIV mono-infected group. All the infected groups had an upregulated expression of the activating receptor NKG2D on CD56.sup.bright NK cells in comparison to healthy controls while not differing amongst themselves. Thus, HIV-HCV co-infection is able to modulate the phenotype of CD56.sup.bright NK cell subset in a unique way such that NKp46 and CXCR3 expressions are distinct for co-infection while both mono-infections have an additive effect on CD56.sup.bright, CD69 with CD95 expressions. HCV mono-infection has a dominant effect on NKp30 expression while NKG2D and CD127 expressions remained same in all the groups.
Summary Background Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of ...an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4×, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24Gag , in adults infected with HIV-1. Methods Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4× with placebo. Participants were adults infected with HIV-1 who were aged 18–55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 106 cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4× or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4× (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov , number NCT00659789. Findings 174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4× and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4× group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference −5·71, 95% CI −13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4× group both at week 48 (median 23 100 copies per mL Vacc-4× vs 71 800 copies per mL placebo; p=0·025) and week 52 (median 19 550 copies per mL vs 51 000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4× was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. Interpretation The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4× was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. Funding Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.
The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA ...byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.
Abstract Background We aimed to compare the non-AIDS events (nADE) risk between normal progressors using ART (NP-ART) and people with HIV (PWH) that naturally control HIV infection (HIV controllers), ...as well as the outcomes after ART in HIV controllers on nADE. Methods The primary endpoint was major nADE defined as the composite of cardiovascular disease, non-AIDS malignancy or all-cause mortality, whichever came first.. The role of ART in HIV controllers was assessed as a time-varying covariate. Results We included 1007 ART-naive HIV controllers (of which 60 elite controllers), 1510 Early-ART (<6 months after negative HIV test) and 15437 NP-ART (reference group), contributing 3813, 11,060 and 160,050 years of follow-up, respectively. HIV controllers had lower risk of the primary endpoint (HR 0.55, 95%CI 0.38-0.81, P = 0.0023), all-cause mortality (Adjusted Hazard ratio aHR: 0.45, 95% confidence interval CI 0.25-0.79, P = 0.0054), cardiovascular disease (aHR 0.47, 95%CI 0.22-0.99, P = 0.046) , but not non-AIDS malignancy (aHR 0.74, 95%CI 0.41-1.35, P = 0.33) than NP-ART. Among HIV controllers, each log10 lower baseline viral load further decreased the risk of nADE (aHR 0.54, 95% CI 0.29-0.99, P = 0.045). ART in HIV controllers did not reduce the risk of any nADE (aHR 1.22, 95% CI 0.66-2.29, P = 0.53). Conclusions We found a lower risk of nADE in HIV controllers than NP-ART, especially in those with low plasma viral loads. Initiation of ART did not alter the nADE risk in HIV controllers. Our findings help clinicians to decide on prescribing ART in HIV controllers.
Most people infected with HIV-1 cannot control viral replication despite the presence of virus-specific CD8+ T cells. It has been postulated that this inability is related to the failure of these ...cells to mature into fully differentiated effector cells. We tested this hypothesis by comparing the maturation phenotype of virus-specific CD8+ T cells in people who could control viral replication off anti-retroviral therapy with those who could not. In five patients with treated acute HIV-1-infection, structured treatment interruption (STI) induced control of viral replication was associated with expansion of virus-specific CD8+ T cells with a fully differentiated effector phenotype. These effector cells were also expanded in treatment-naive chronically infected individuals who spontaneously controlled viral replication, and augmented expression of perforin was noted in both settings. Our data show that full maturation of virus-specific CD8+ T cells is possible in the context of HIV-1-infection, and suggest that such maturation might be important in viral control.
To compare the safety and efficacy of the two single-tablet regimens (STRs), rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir DF ...(EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults.
This is a phase 3b, randomized, open-label, multicenter, international, 96-week study.
Participants were randomized 1:1 to receive either RPV/FTC/TDF or EFV/FTC/TDF. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies/ml at week 48 by the Snapshot algorithm.
A total of 786 participants were randomized. RPV/FTC/TDF was noninferior to EFV/FTC/TDF (85.8 vs. 81.6%) at week 48 for HIV-1 RNA less than 50 copies/ml difference 4.1%, 95% confidence interval (CI) -1.1 to 9.2%. A statistically significant difference in efficacy favoring RPV/FTC/TDF was demonstrated for participants with baseline HIV-1 RNA 100000 copies/ml or less (n=510) 88.8% RPV/FTC/TDF vs. 81.6% EFV/FTC/TDF (difference 7.2%, 95% CI 1.1-13.4%). In participants with baseline HIV-1 RNA more than 100000 copies/ml (n=276), RPV/FTC/TDF demonstrated noninferior efficacy compared with EFV/FTC/TDF (79.9 vs. 81.7%, respectively, difference -1.8%, 95% CI -11.1 to 7.5%). In the RPV/FTC/TDF arm, more virologic failure was observed as baseline HIV-1 RNA levels increased. There were more participants with emergent resistance in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm (4 vs. 1%, respectively). There were fewer discontinuations because of adverse events with RPV/FTC/TDF (2.5%) than with EFV/FTC/TDF (8.7%).
In treatment-naive participants, RPV/FTC/TDF demonstrated noninferior efficacy and improved tolerability compared with EFV/FTC/TDF, as well as a statistically significant difference in efficacy for participants with baseline HIV-1 RNA 100000 copies/ml or less at week 48.
Current combination antiretroviral therapies (cART) efficiently suppress HIV-1 reproduction in humans, but the virus persists as integrated proviral reservoirs in small numbers of cells. To generate ...an antiviral agent capable of eradicating the provirus from infected cells, we employed 145 cycles of substrate-linked directed evolution to evolve a recombinase (Brec1) that site-specifically recognizes a 34-bp sequence present in the long terminal repeats (LTRs) of the majority of the clinically relevant HIV-1 strains and subtypes. Brec1 efficiently, precisely and safely removes the integrated provirus from infected cells and is efficacious on clinical HIV-1 isolates in vitro and in vivo, including in mice humanized with patient-derived cells. Our data suggest that Brec1 has potential for clinical application as a curative HIV-1 therapy.
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