Imbalanced production of cytokines by T cells associates with the activation/exhaustion status of memory T cells in chronic HIV type 1 infection.

Chronic HIV-1 infection is characterized by immune cell dysfunctions driven by chronic immune activation. Plasma HIV-1 viral load (VL) is closely correlated with disease progression and the level of immune activation. However, the mechanism by which the persistent presence of HIV-1 damages immune cells is still not fully understood. To evaluate how HIV-1 affects disruption of T cell-mediated immune responses during chronic HIV-1 infection we determined the functional profiles of T cells from subjects with chronic HIV-1 infection. We measured the capacity of peripheral blood mononuclear cells (PBMCs) to produce 25 specific cytokines in response to nonspecific T cell stimulation, and found that the capacity to produce Th-1-related cytokines (MIP-1α, MIP-1β, RANTES, IFN-γ, and MIG), sIL-2R, and IL-17, but not Th-2-related cytokines, was inversely correlated with plasma VL. The capacities to produce these cytokines were interrelated; notably, IL-17 production had a strong direct correlation with production of MIP-1α, MIP-1β, RANTES, and IFN-γ. In both CD4(+) and CD8(+) T cells, dysfunctional production of cytokines was associated with T cell activation (CD38 expression) and exhaustion (PD-1 and/or CTLA-4 expression) status of memory subsets. Although the capacity to produce these cytokines was recovered soon after multiple log(10) reduction of plasma viral levels by antiretroviral therapy, memory CD8(+) T cells remained activated and exhausted after prolonged virus suppression. Our data suggest that HIV-1 levels directly affect the ability of memory T cells to produce specifically Th1- and Th17-related cytokines during chronic HIV-1 infection.