CD4+ T Cell Immunity in Human Immunodeficiency Virus

While antiretroviral therapy (ART) controls human immunodeficiency virus (HIV) viremia and restores CD4+ T cell counts in most people with HIV (PWH), there is still no cure for HIV. The kinetics of ART-mediated immune restoration require further investigation to inform the development and testing of immunotherapeutics to achieve HIV cure. I characterized immune restoration in two longitudinal cohorts of PWH, one post-ART initiation and the other years after viral suppression, with a focus on CD4+ T cell clonotype, phenotype and function. Leukocyte lineages, including CD4+ T cell memory, were stable in PWH on long-term ART. By contrast, in the post-ART window, broad but shared changes in leukocyte populations were observed. Against this backdrop of dynamic immune restoration, both absolute frequencies and hierarchies of dominant CD4+ TCR clonotypes were stable over time, suggesting that CD4+ T cell clonal homeostasis is maintained independently of homeostatic processes that regulate CD4+ T cell number, phenotype and function. I also performed cross-sectional analysis of healthy donors (HD) and PWH that were durably suppressed treated during either acute (AHI) or chronic infection. Within PWH treated during chronic infection, I examined two groups: PWH who restored CD4+ T cell counts >350 cells/mm3 (CHI) and PWH who did not (INR). During untreated infection, there is a decrease in CD127 and IL-7 responsiveness in T cells. STAT5 phosphorylation (pSTAT5) analysis, which is downstream of IL-7 signaling, showed that CHI had lower basal pSTAT5 compared to HD. However, we did not observe basal pSTAT5 dysregulation in INR, possibly due to higher plasma IL-7 in this group. Deep immune profiling found that durably suppressed AHI restored phenotypes were comparable to HD and that INR had a higher frequency of effector memory CD4+ T cells compared to HD. Overall, these data suggest that restoration and homeostasis of CD4+ T cells in PWH is multi-factorial, including timing of ART initiation, duration of viral suppression and CD4+ T cell count. This work directly informs the design of immunotherapeutic studies in PWH including ART treatment interruption to assess post-treatment HIV control, an approach that is increasingly used as an efficacy measure in HIV cure studies.