Sex Influences SAMHD1 Activity and Susceptibility to Human Immunodeficiency Virus-1 in Primary Human Macrophages
Year: 2018
Type: article
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.
Institutions: University of Utah, George Washington University
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1864519198, BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy, BELIEVE: Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication, G3450047942, Modulating Immune Senescence of Effector Lymphocytes in Chronic HIV Infection, Preclinical Development of Ingenol and HDACi Toward HIV Eradication, Research Training in Hematology, The Effects of ART on Platelets and HIV-Associated Thrombosis, Preclinical Development of Ingenol and HDACi Toward HIV Eradication
OpenAlex ID: W2896804758