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.