CTLA-4⁺PD-1⁻ Memory CD4⁺ T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques

Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1⁺ follicular helper T (Tfh) cells as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4⁺PD-1⁻ memory CD4⁺ T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus. In contrast to PD-1⁺ Tfh cells, SIV-enriched CTLA-4⁺PD-1⁻ CD4⁺ T cells were found outside the B cell follicle of the LN, predicted the size of the persistent viral reservoir during ART, and significantly increased their contribution to the SIV reservoir with prolonged ART-mediated viral suppression. We have shown that CTLA-4⁺PD-1⁻ memory CD4⁺ T cells are a previously unrecognized component of the SIV and HIV reservoir that should be therapeutically targeted for a functional HIV-1 cure. HIV persists in T follicular helper cells within the lymph node during antiretroviral therapy, but decays with time. McGary et al. identify the persistence of replication-competent SIV and HIV outside the lymph node follicle in a unique subset of CTLA-4⁺PD-1⁻ memory CD4⁺ T cells that share features with regulatory T cells.