Type I IFN-mediated sex differences in immune responses to HIV-1

• Applicant: Professor Dr. Marcus Altfeld
• Subject Area: Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

The manifestations of HIV-1 infection differ between cis-gender women living with HIV-1 (WLWH) and cis-gender men living with HIV-1 (MLWH), including better control of viral replication during acute infection but faster loss of CD4+ T cells during untreated chronic HIV-1 infection in WLWH. Increasing data indicate an important contribution of sex-specific differences in Type I IFN responses to these sex differences in the manifestation of HIV-1 disease. In previous studies, we demonstrated that pDCs derived from women produce more IFNα in response to HIV-1-derived TLR7 ligands than pDCs from men. During the first funding period, we showed that TLR7-induced Type I IFN responses are reduced in trans men following initiation of gender-affirming testosterone treatment (GAHT), while molecules enhancing TLR7-induced Type I IFN production, such as DDX3X that is encoded by the X chromosome, can escape X chromosomal inactivation (XCI), resulting in higher expression and stronger IFNα production. We furthermore demonstrated that stronger Type I IFN responses in women result in stronger activation of antiviral NK cells and are associated with smaller intact proviral HIV-1 reservoirs in CD4+ T cells in WLWH on antiretroviral therapy (ART). In the second funding period, we plan to build on these observations and further delineate the molecular mechanisms by which sex hormones and genes located on the X chromosome affect Type I IFN responses of pDCs, and the consequences for antiviral immunity in HIV-1 infection. For these studies, we will take advantage of the unique longitudinal sample repository collected from the Hamburg Transgender Cohort that was established through the RU 5068. We will furthermore use next-generation long-read single-cell RNA sequencing approaches to more comprehensively investigate the combined role of genes located on the X chromosome that escape XCI on Type I IFN responses. Taken together, these studies will identify critical mechanisms underlying sex-specific differences in Type I IFN-mediated antiviral immunity, and provide rationale for the design of interventions that take these differences into account.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity