Type I IFN-mediated sex differences in immune response to HIV-1
In acute HIV-1 infection, women control viral replication better than men. In contrast, women develop increased immune activation and faster loss of CD4+ T cells during untreated chronic HIV-1 infection. Increasing data indicate that these sex differences in the manifestation of HIV-1 disease are mediated by sex-specific differences in antiviral immunity. In previous studies we demonstrated that pDCs derived from women produce more IFNα in response to HIV-1 than pDCs from men, potentially contributing to the better control of viremia in acute infection. This increased IFNα production in response to HIV-1 however also led to significantly higher immune activation and faster loss of CD4+ T cells in chronically HIV-1-infected women. Taken together these data strongly suggest that sex differences in Type I IFN production result in differences in HIV-1 disease manifestations between women and men. However, the precise molecular mechanisms underlying these sex differences in HIV-1 and other infectious diseases remain poorly understood. We hypothesize that X chromosome-encoded genes play a critical role in regulating Type I IFN responses, and that gene-dose effects resulting from escape from X chromosome inactivation (XCI) contribute to sex-specific differences in antiviral immunity, using HIV-1 as a model. We will furthermore test the hypothesis that changes in levels of sex hormones can regulate Type I IFN responses of pDCs, using longitudinal samples from a human transgender cohort. Taken together, these studies will identify critical mechanisms underlying sex-specific differences in antiviral immunity, and provide rationale for the design of interventions that take these differences between women and men into account.
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