Background:  LCMV models indicate that interleukin (IL) -10 and PD-1 suppress viral clearance. HIV-1 infection is characterized by T cell dysfunction that correlates with increased serum IL-10 and PD-1 expression on virus-specific T cells. Blockade of IL-10 or PD-1 can restore CD4 T cell proliferation in some HIV-1⁺ individuals, but the types of subjects that respond to these interventions is not defined, and it is unknown whether these pathways act additively or redundantly to inhibit T cell function. Therefore, we examined IL-10 production and the effect of IL-10 and PD-1 blockade on CD4 T cell proliferation in different cohorts of HIV-1⁺ individuals.

Methods:  Peripheral blood mononuclear cells (PBMC) were obtained from HIV⁺ individuals (n = 40) displaying a range of viral loads, CD4 counts, and therapy status, as well as uninfected controls (n = 10). IL-10 mRNA was analyzed by real-time polymerase chain reaction (RT-PCR) in PBMC and bead-sorted CD3⁺, CD19⁺, CD14⁺, and CD11b⁺ subsets. CD4 T cell function was examined using CFSE-based proliferation assays (n = 20) in the absence or presence of IL-10 Ra or PD-L1 blocking antibodies.

Results:  Significantly higher levels of IL-10 mRNA were observed in viremic HIV-1⁺ subjects than in spontaneous HIV-1 controllers or uninfected persons (p <0.001, Kruskal-Wallis). IL-10 was higher in numerous cell types (B cells, T cells, monocytes), correlated with plasma viremia (r = 0.64, p = 0.003, Spearman), and declined following initiation of ART. Median CD4 T cell proliferation in response to HIV-1 p24 or CMV antigen was enhanced 3-fold by blockade of IL-10 in viremic subjects (p = 0.016, Wilcoxon), but not in aviremic individuals. Notably, subjects with higher viremia responded better to IL-10 blockade than to PD-1 blockade, and we observed an additive effect of blocking both in some individuals.

Conclusions:  These results indicate that IL-10 production correlates with HIV-1 disease progression and that IL-10 mediates dysfunction of virus-specific CD4 T cells in viremic subjects that is reversible upon IL-10 Ra blockade. Furthermore, during chronic HIV-1 infection, IL-10 and PD-1 likely function independently. Deletion or blockade of both pathways during therapeutic immunization may enhance the efficacy of current HIV vaccines.