Role of IL-32 in HIV Reactivation and its Link to HIV-HSV Coinfection

Abstract

Background. Herpes simplex virus type 2 (HSV-2; herpes) exacerbates human immunodeficiency virus type 1 (HIV) by unclear mechanisms. These studies tested the impact of HSV-2 on systemic T-cells and HIV reservoirs. Methods. Peripheral blood mononuclear cells from HIV-infected women on antiretroviral therapy who were HSV-2 seroposi-tive or seronegative and HIV-uninfected controls were analyzed by flow cytometry. Cell-associated HIV DNA and RNA were quan-tified in the absence or presence of activating stimuli, recombinant interleukin 32γ (IL-32γ), and a RUNX1 inhibitor. RNA was assessed by nanostring. Results. CD4, but not CD8, T-cell phenotypes differed in HIV + /HSV-2 + versus HIV + /HSV-2 − (overall P = .002) with increased frequency of CCR5 + , CXCR4 + , PD-1 + , and CD69 + and decreased frequency of CCR10 + and CCR6 + T-cells. The changes were asso-ciated with higher HIV DNA. Paradoxically, IL-32, a proinflammatory cytokine, was lower in subpopulations of CD4 + T-cells in HSV-2 + versus HSV-2 − women. Recombinant IL-32γ blocked HIV reactivation in CD4 + T-cells and was associated with an increase in RUNX1 expression; the blockade was overcome by a RUNX1 inhibitor. Conclusions. Herpes is associated with phenotypic changes in CD4 + T-cells, including a decrease in IL-32, which may contrib-ute to increased HIV reservoirs. Blocking IL-32 may facilitate HIV reactivation to improve shock and kill strategies.