Activated PD-1⁺ CD4⁺ T cells represent a short-lived part of the viral reservoir and predict poor immunologic recovery upon initiation of ART

Objective: Activated (CD38⁺HLA-DR⁺) PD-1⁺ CD4⁺ T cells are strongly associated with virus replication and disease progression in untreated HIV-1 infection, and viral persistence in individuals on ART. Few studies have examined cell-associated viral load (CAVL) in different activated CD4⁺ T-cell populations to measure relative contributions to viral reservoirs.Design:Longitudinal assessment of HIV-1 chronically infected Ugandans initiating ART, to investigate activated CD4⁺ T-cell populations and their contribution to viral reservoirs.Methods:We followed 32 HIV-1 chronically infected individuals from Kampala, Uganda, and determined their CD4⁺ T-cell counts and viral load at baseline, 6, and 12 months after the initiation of ART. T-cell populations were sorted based on activation profiles and gag DNA was measured to determine CAVL within these populations. Soluble factors associated with inflammation were measured in plasma using a multiplexed platform.Results:Concomitant with viral load decline and CD4⁺ T-cell count rebound, the activated PD-1⁺ CD4⁺ T-cell population contracted upon initiation of ART. Baseline levels of activated PD-1⁺ CD4⁺ T cells correlated with plasma levels of IP-10 and TNFRII. Interestingly, a higher baseline level of activated PD-1⁺ CD4⁺ T cells was associated with poorer CD4⁺ T-cell recovery after 12 months of ART. This population contributed significantly to the cell-associated HIV DNA load at baseline, whereas their contribution declined on ART, indicating high turnover.Conclusion:Activated PD-1⁺ CD4⁺ T cells are predictors of poor immunologic recovery on ART and may represent a short-lived component of HIV-1 reservoirs.