Role of Interleukin 32 in Human Immunodeficiency Virus Reactivation and Its Link to Human Immunodeficiency Virus-Herpes Simplex Virus Coinfection

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 seropositive or seronegative and HIV-uninfected controls were analyzed by flow cytometry. Cell-associated HIV DNA and RNA were quantified in the absence or presence of activating stimuli, recombinant interleukin 32 gamma (IL-32 gamma), 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 associated 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-32. 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 contribute to increased HIV reservoirs. Blocking IL-32 may facilitate HIV reactivation to improve shock and kill strategies.