Impact of early antiretroviral treatment on tissue resident memory CD4+ T cells in the gastrointestinal tract.

Abstract

Tissue resident memory CD4+ T cells (CD4+ TRM) are long-lived, seldom-circulating cells that reside for long periods in most tissues. TRM can mount rapid, antigen-specific responses to pathogens and contribute to mucosal barrier homeostasis by regulating commensal interactions. At the intestinal mucosa, the main site of early HIV replication, CD4+ TRM may serve as virus targets; however, limited data are available regarding their dynamics during acute HIV-1 infection and antiretroviral treatment. Nested cross-sectional study within a longitudinal cohort. Sigmoid CD4+ TRM (CD69+CD103+) had a higher expression of CCR5 compared to CD4+ non-TRM (CD69-CD103-), suggestive of increased susceptibility to HIV-1 infection. Consistent with this, sigmoid CD4+ TRM but not CD4+ non-TRM were depleted/non-replenished despite long-term ART, regardless of the Fiebig (F) stage treatment was initiated during acute HIV infection. In contrast, overall sigmoid CD4+ T-cells were comparable in abundance with people living without HIV if treatment was initiated in FI/II, but were significantly decreased if treatment was initiated >FIII, suggesting preferential early depletion/non-replenishment of CD4+ TRM. The loss/non-replenishment of sigmoid CD4+ TRM was associated with a lower abundance of short-chain fatty acid producing commensal bacteria that are crucial for the maintenance of mucosal homeostasis, a higher abundance of opportunistic pathobionts Desulfovibrio, and increased soluble biomarkers of systemic inflammation that drive non-AIDS mortality. Sigmoid CD4+ TRM may be early mucosal targets of HIV-1 infection and that their persistent depletion contributes to decreased mucosal barrier function, warranting development of therapeutic strategies that can restore CD4+ TRM during HIV treatment.