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.

Project description:Despite the critical role antigen-specific T cells play in containing viral infections, their aggregate frequencies in peripheral blood have not correlated with clinical protection during HIV infection. However, a subset of HIV-specific T cells, which are capable of simultaneously producing multiple effector cytokines, termed polyfunctional T cells, have correlated with delayed disease progression. HIV-specific polyfunctional T cells have been enumerated and characterized using the intracellular cytokine staining (ICS) assay, which allows for simultaneous multiplexed analysis of cytokine expression at the single-cell level. In addition, using an unbiased computational analysis of ICS data generated through the RV144 HIV vaccine case-control study, we identified vaccine-induced HIV envelope (Env)-specific polyfunctional CD4 T cells as a novel correlate of reduced risk of HIV infection. However, very little is known about these cells and what differentiates them from other vaccine-elicited T cells. In addition, the use of sample fixation in the ICS assay prevents those cells from being further interrogated for transcriptional differences. Thus, we developed a novel live-cell multiplexed cytokine capture assay which allows for identification, sorting and transcriptional profiling of individual antigen-specific polyfunctional T cells by single-cell RNA-sequencing (scRNA-seq). We applied these methods to peripheral blood samples from participants who had received the RV144 vaccine regimen as part of the HVTN 097 clinical trial. Using this approach, we discovered transcriptional signatures that specifically identify the single-cell Env-specific CD4 T-cell functional profiles which had correlated with reduced risk of HIV infection in RV144. Interestingly, this signature is particularly characterized by upregulation of Th2 cytokines, supporting the hypothesis that the vaccine-induced Env-specific CD4 T cells likely contributed to the reduced risk of infection by providing T cell help to the Env-specific antibody responses. By interrogating the gene signatures that correlated with polyfunctionality, we have identified potential mechanisms of how vaccine-elicited polyfunctional T cells may contribute to reduced risk of HIV infection.

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Loss of CD4 T cell responses to prior vaccines associate with inflammation and altered transcriptional signatures in HIV infection

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