Project description:HIV-1 infection of resting memory CD4+ T cells forms a barrier to curing HIV-1. Identification of immune biomarkers that correlate with HIV-1 reservoir size could aid with assessing efficacy of HIV-1 eradication strategies, especially in pediatric infections where blood sampling is limited. In adults, the immune exhaustion marker PD-1 on central memory CD4+ T cells (Tcm) correlates with HIV-1 reservoir size. Immune correlates of HIV-1 reservoir size are less defined in perinatal infection. Using multi-parameter flow cytometry, we examined immune activation (CD69, CD25, HLA-DR), and exhaustion (PD-1, TIGIT, LAG-3 and TIM-3) markers on CD4+ T cell subsets (naïve (Tn), central memory (Tcm), and a combination (Ttem) of transitional (Ttm) and effector memory (Tem) in 10 children living with HIV-1 (median age 15.9 years; median duration of virologic suppression 7.0 years), in whom HIV-1 reservoir size was determined with both the Intact Proviral HIV-1 DNA assay (IPDA) and the Tat/Rev limiting dilution assay (TILDA). Total HIV-1 DNA in CD4+ T cells was also measured. Correlations between immune activation, and exhaustion markers on T cell subsets with the various markers of proviral reservoir size, and baseline CD4+ T cell transcriptomes were examined. The median total HIV-1 DNA concentration was 211.9 copies per million CD4+ T cells, with a median intact proviral load in individuals with HIV-1 subtype B of 8.0 copies per million CD4+ T cells. Levels of HLA-DR and TIGIT on Ttem were strongly correlated with total HIV-1 DNA (r=0.758, p=0.015) and (r=0.721, p=0.023), respectively, but not with intact proviral load or inducible reservoir size. HIV-1 DNA load was also positively correlated with transcriptional clusters associated with HLA-DR. In contrast, PD-1 expression on Tcm was inversely correlated with both total HIV-1 DNA (r=-0.67, p=0.039) and HLA-DR in Ttem (r=-0.89, p=0.060). Gene expression profiles for HLA-DR and PD-1 were also inversely correlated. In conclusion, with virologically suppressed perinatal HIV-1 infection, HLA-DR and TIGIT on Ttem CD4+ T cells correlate with total HIV-1 DNA, and may serve as immune biomarkers for transcriptionally active proviruses, including defectives persisting on ART.

Project description:Without treatment, HIV-1 infection is characterized in the majority of individuals by a detectable HIV replication and a rapid decline in CD4+ T lymphocytes leading to AIDS. However, a minority of patients, called “HIV Controllers” (HIC), maintains spontaneous control of HIV replication and for a large part, normal CD4+ T cell counts. The mechanisms leading to this spontaneous virus control are not fully known. We used gene expression and functional cellular analyses to compare EC and chronically HIV-1 infected individuals with controlled virus replication under combined antiretroviral therapy (cART). In the blood, EC individuals are characterized by a low inflammation, a down modulation of NK inhibitory cell signaling and an up regulation of T-cell activation gene expression profiles. Interestingly, in contrast to cART individuals, this balance persists following in vitro stimulation of cells from HIC with HIV antigens. This favourable genetic profile in HIC was also consistent with functional analyses showing a bias towards a Th1 and cytotoxic T cell profile and a lower production of inflammatory cytokines. Finally, taking advantage of the characterization of HIC based upon their in vitro CD8+ T lymphocyte capacity of killing HIV-infected cells, we show that unsupervised genetic analysis of differentially expressed genes fits clearly with this cytotoxic activity allowing the characterization of a specific signature of HIC individuals. Globally, these results reveal significant features of HIC making the bridge between cellular function and gene signatures and the regulation of inflammation and killing capacity of HIV-specific CD8+T cells. Moreover, these genetic profiles are consistent through analyses performed from whole blood to PBMC and at the T-cell population levels. Likely, these data help to define the goals of immunotherapeutic approaches in the perspective of HIV-1 functional cure. These strategies would need to induce both strong HIV-1-specific immune responses whereas minimizing inflammation.

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NK cells actively control HIV-1 DNA reservoir

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