Estradiol Reduces Susceptibility of CD4+ T Cells and Macrophages to HIV-Infection

The magnitude of the HIV epidemic in women requires urgent efforts to find effective preventive methods. Even though sex hormones have been described to influence HIV infection in epidemiological studies and regulate different immune responses that may affect HIV infection, the direct role that female sex hormones play in altering the susceptibility of target cells to HIV-infection is largely unknown. Here we evaluated the direct effect of 17-beta-estradiol (E-2) and ethinyl estradiol (EE) in HIV-infection of CD4(+) T-cells and macrophages. Purified CD4(+) T-cells and monocyte-derived macrophages were generated in vitro from peripheral blood and infected with R5 and X4 viruses. Treatment of CD4(+) T-cells and macrophages with E-2 prior to viral challenge reduced their susceptibility to HIV infection in a dose-dependent manner. Addition of E-2 2 h after viral challenge however did not result in reduced infection. In contrast, EE reduced infection in macrophages to a lesser extent than E-2 and had no effect on CD4(+) T-cell infection. Reduction of HIV-infection induced by E-2 in CD4(+) T-cells was not due to CCR5 down-regulation, but was an entry-mediated mechanism since infection with VSV-G pseudotyped HIV was not modified by E-2. In macrophages, despite the lack of an effect of E-2 on CCR5 expression, E-2-treatment reduced viral entry 2 h after challenge and increased MIP-1 beta secretion. These results demonstrate the direct effect of E-2 on susceptibility of HIV-target cells to infection and indicate that inhibition of target cell infection involves cell-entry related mechanisms.