Differential Effect of Cytokines on CD4+ T-Cell Activation, Metabolism, and Susceptibility to HIV-1 Infection

HIV-1 reservoirs are predominantly located in CD4+ T-cells; however, not all CD4+ T-cells contribute to the reservoir in the same way. Factors such as activation, differentiation, and cell metabolism have been proposed to determine the relative susceptibility of cells to HIV-1 infection. HIV-1 reservoirs are seeded early during the acute phase of infection, but the cell composition of these reservoirs evolves in the transition to chronic infection. This suggests that there are factors during the acute phase that may alter the intrinsic susceptibility of CD4+ T-cells to HIV-1. We investigated here the influence of common cytokines known to be secreted during the acute phase and to play a role in either T cell homeostasis or HIV-1 infection on activation, differentiation, metabolic activity, and HIV-1 susceptibility of CD4+ T-cells. We show that the proinflammatory cytokines interleukin (IL)-2, IL-7, and IL-15 induce cellular activation, differentiation to effector profile, increase in metabolic capacity, and HIV-1 susceptibility. In contrast, IL-21, another cytokine from the gamma-chain (γc) family, showed opposing effects on the same parameters, including decreasing oxidative phosphorylation (OXPHOS) and HIV-1 infection. We also show that IL-10 and interferon (IFN)-α are able to at least partially revert the cellular and metabolic changes induced by IL-2 or IL-7 and reduce the cells' susceptibility to HIV-1.