HIV infection results in excessive T cell activation and dysfunction which may persist even during effective antiretroviral therapy (ART). The dynamics of immune 'deactivation' and extent to which T cell memory subsets normalize after ART are unclear. We longitudinally assessed the influence of 1 year of ART on the phenotype of T cells in HIV-infected African women, relative to matched HIV-uninfected women, using activation (CD38, HLA-DR) and differentiation markers (CD27, CD45RO). ART induced a substantial reduction in T cell activation, but remained higher than HIV-uninfected controls. ART largely normalized the distribution of CD4+ T cell memory subsets, while the distribution of CD8+ T cell memory subsets remained significantly skewed compared to HIV-uninfected individuals. Thus, there was a considerable but only partial reversal of T cell defects upon ART. Understanding T cell impairment may provide important insights into mechanisms of HIV pathogenesis in the era of ART.

BackgroundThe majority of people living with HIV require antiretroviral therapy (ART) for controlling viral replication, however there are rare HIV controllers who spontaneously and durably control HIV in the absence of treatment. Understanding what mediates viral control in these individuals has provided us with insights into the immune mechanisms that may be important to induce for a vaccine or functional cure for HIV. To date, few African elite controllers from high incidence settings have been described. We identified virological controllers from the CAPRISA 002 cohort of HIV-1 subtype C infected women in KwaZulu Natal, South Africa, two (1%) of whom were elite controllers. We examined the genetic, clinical, immunological and virological characteristics of these two elite HIV controllers in detail, to determine whether they exhibit features of putative viral control similar to those described for elite controllers reported in the literature.Case presentationIn this case report, we present clinical features, CD4+ T cell and viral load trajectories for two African women over 7 years of HIV infection. Viral load became undetectable 10 months after HIV infection in Elite Controller 1 (EC1), and after 6 weeks in Elite Controller 2 (EC2), and remained undetectable for the duration of follow-up, in the absence of ART. Both elite controllers expressed multiple HLA Class I and II haplotypes previously associated with slower disease progression (HLA-A*74:01, HLA-B*44:03, HLA-B*81:01, HLA-B*57:03, HLA-DRB1*13). Fitness assays revealed that both women were infected with replication competent viruses, and both expressed higher mRNA levels of p21, a host restriction factor associated with viral control. HIV-specific T cell responses were examined using flow cytometry. EC1 mounted high frequency HIV-specific CD8+ T cell responses, including a B*81:01-restricted Gag TL9 response. Unusually, EC2 had evidence of pre-infection HIV-specific CD4+ T cell responses.ConclusionWe identified some features typical of elite controllers, including high magnitude HIV-specific responses and beneficial HLA. In addition, we made the atypical finding of pre-infection HIV-specific immunity in one elite controller, that may have contributed to very early viral control. This report highlights the importance of studying HIV controllers in high incidence settings.Electronic supplementary materialThe online version of this article (10.1186/s12879-018-2961-8) contains supplementary material, which is available to authorized users.

Antiretroviral therapy (ART) induces rapid suppression of viral replication and a progressive replenishment of CD4+ T cells in HIV-infected individuals. However, the effect of ART on restoring pre-existing memory CD4+ T cells specific for common co-pathogens is still unclear. To better understand the dynamics of antigen-specific CD4+ T cells during ART, we assessed the frequency, functional capacity and memory profile of CD4+ T cells specific for Mycobacterium tuberculosis (Mtb) and cytomegalovirus (CMV) in 15 HIV-infected individuals before and one year after ART initiation. After ART initiation, the frequency of Mtb-specific CD4+ T cells showed little change, while CMV-specific CD4+ T cells were significantly lower (p=0.003). There was no difference in the polyfunctional or memory profile of antigen-specific CD4+ T cells before and after ART. The replenishment of antigen-specific CD4+ T cells correlated with the memory differentiation profile of these cells prior to ART. Pathogen-specific CD4+ T cells exhibiting a late differentiated profile (CD45RO+CD27−) had a lower capacity to replenish (p=0.019, r=−0.5) compared to cells with an early differentiated profile (CD45RO+CD27+; p=0.04, r=0.45). In conclusion, restoration of co-pathogen-specific memory CD4+ T cells during treated HIV infection is related to their memory phenotype, where early differentiated cells (such as most Mtb-specific cells) have a higher replenishment capacity compared to late differentiated cells (such as most CMV-specific cells). These data identify an important, hitherto unrecognized, factor that may limit restoration of co-pathogen immunity in HIV-infected individuals on ART.

Background Adolescents in sub-Saharan Africa are at risk for HIV infection and unintended pregnancies. Observational studies suggest that injectable hormonal contraceptives (HC) increase HIV risk, although their effects on genital inflammation, particularly HIV-susceptible Th17 cells, are unknown. In a randomized cross-over study, the effect of injectable norethisterone oenanthate (NET-EN), combined contraceptive vaginal rings (CCVR; NuvaRing®), and combined oral contraceptive pills (COCPs) on cervical Th17 cells and cytokines were compared. Methods Adolescents (n=130; 15-19 years), randomized 1:1:1 to NET-EN, CCVR, or COCPs for 16-weeks, subsequently crossed-over to another HC for 16-weeks. Estrogen (E2), follicular stimulating hormone (FSH), and luteinizing hormone (LH) were measured. CCR5, HLA-DR and CD38 expression by cervical cytobrush-derived CD4+ T cells was assessed by FACS. Th17 cells were defined as CCR6+CCR10-. Cervicovaginal Th17-related cytokines were measured by Luminex. Results CCVR use for the first 16-weeks was associated with reduced Th17 frequencies and lower FHS and LH concentrations compared to NET-EN/COCPs, with FHS concentrations and Th17 frequencies correlating significantly. However, Th17-related cytokine concentrations (IL-21, IL-1β, TNF-α, IFN-γ) and CCR5+HLA-DR+CD38+ Th17 frequencies were significantly higher in CCVR than NET-EN/COCP. At cross-over, CCVR users changing to COCPs or NET-EN did not resolve activation or cytokines, although switching from COCP to CCVRs increased cytokine concentrations. Conclusion CCVR use altered endogenous hormone levels and associated cervical Th17 cell frequencies to greater extent than NET-EN/COCPs, although Th17 cells were more activated and Th17-related cytokine concentrations were elevated. While CCVRs may impact HIV risk by regulating Th17 numbers, increased activation/inflammation may balance any risk gains.

HIV infection induces a wide range of effects in B cells, including skewed memory cell differentiation, compromised B cell function and hypergammaglobulinaemia. However, data on the extent to which these B cell abnormalities can be reversed by antiretroviral therapy (ART) are limited. To investigate the effect of ART on B cells, the activation (CD86) and differentiation (IgD, CD27 and CD38) profiles of B cells were measured longitudinally in 19 HIV-infected individuals before (median, 2 months) and after ART initiation (median, 12 months) and compared to 19 age-matched HIV-uninfected individuals, using flow cytometry. Twelve months of ART restored the typical distribution of B cell subsets, increasing the proportion of naive B cells (CD27−IgD+CD38−) and concomitantly decreasing the immature transitional (CD27−IgD+CD38+), unswitched memory (CD27+IgD+CD38−), switched memory (CD27+IgD−CD38− or CD27−IgD−CD38−) and plasmablast (CD27+IgD−CD38high) subsets. However, B cell activation was only partially normalized post-ART, with the frequency of activated B cells (CD86+CD40+) reduced compared to pre-ART levels (p=0.0001), but remaining significantly higher compared to HIV-uninfected individuals (p=0.0001). Interestingly, unlike for T cell activation profiles, the extent of B cell activation prior to ART did not correlate with HIV plasma viral load, but positively associated with plasma sCD14 levels (p=0.01, r=0.58). Overall, ART partially normalizes the skewed B cell profiles induced by HIV, with some activation persisting. Understanding the effect of HIV on B cell dysfunction and restoration following ART may provide important insights into mechanisms of HIV pathogenesis.