Sex Influences SAMHD1 Activity and Susceptibility to Human Immunodeficiency Virus-1 in Primary Human Macrophages

Abstract Background Macrophages are major targets for HIV-1, contribute to viral propagation in vivo, and are instrumental in the pathogenesis of HAND. While it is known that host sex affects HIV-1 viremia and influences the severity of HIV-1-associated neurocognitive disease, a cellular or molecular basis for these findings remains elusive. Methods We explored whether sex affects HIV-1 infectivity of primary human macrophages and CD4+ T cells in vitro. Results Macrophages derived from female donors were less susceptible to HIV-1 infection than those derived from males. This sex-dependent difference in macrophage infectivity was independent of the requirement for CD4/CCR5-mediated virus entry and was not observed in CD4+ T cells. Investigations into the mechanism governing these sex-dependent differences revealed that the host restriction factor SAMHD1 exists in a hyperphosphorylated, less active state in male-derived macrophages. In addition, the major kinase responsible for SAMHD1 phosphorylation, CDK1, exhibited lower levels of expression in female-derived macrophages in all tested donor pairs. The sex-dependent differences in viral restriction imposed by SAMHD1 were abrogated upon its depletion. Conclusions We conclude that SAMHD1 is an essential modulator of infectivity in a sex-dependent manner in macrophages, constituting a novel component of sex differences in innate immune control of HIV-1. SAMHD1 exhibits sex-dependent differences in activity in primary macrophages. We observed increased SAMHD1 activity in macrophages from female donors relative to males, which correlated with and explained the lower infectivity of HIV-1 in female-derived macrophages.