Seminal Plasma Exposures Strengthen Vaccine Responses in the Female Reproductive Tract Mucosae

Abstract

HIV-1 sexual transmission occurs mainly via mucosal semen exposures. In the female reproductive tract (FRT), seminal plasma (SP) induces physiological modifications, including inflammation. An effective HIV-1 vaccine should elicit mucosal immunity, however, modifications of vaccine responses by the local environment remain to be characterized. Using a modified vaccinia virus Ankara (MVA) as a vaccine model, we characterized the impact of HIV-1+ SP intravaginal exposure on the local immune responses of non-human primates. Multiple HIV-1+ SP exposures did not impact the anti-MVA antibody responses. However, SP exposures revealed an anti-MVA responses mediated by CD4+ T cells, which was not observed in the control group. Furthermore, the frequency and the quality of specific anti-MVA CD8+ T cell responses increased in the FRT exposed to SP. Multi-parameter approaches clearly identified the cervix as the most impacted compartment in the FRT. SP exposures induced a local cell recruitment of antigen presenting cells, especially CD11c+ cells, and CD8+ T cell recruitment in the FRT draining lymph nodes. CD11c+ cell recruitment was associated with upregulation of inflammation-related gene expression after SP exposures in the cervix. We thus highlight the fact that physiological conditions, such as SP exposures, should be taken into consideration to test and to improve vaccine efficacy against HIV-1 and other sexually transmitted infections.

Protective efficacy of the anti-HIV broadly neutralizing antibody PGT121 in the context of semen exposure

“…Thus, it is foreseeable that in the correct environment semen could enhance the responsiveness of immune cells. Indeed, a recent study in non-human primates highlighted that exposure to human seminal plasma enhanced mucosal responsiveness to vaccination [37] . As such, it remains unknown if semen is immunosuppressive within anogenital tissues.…”

Extracellular vesicles from seminal plasma interact with T cells in vitro and drive their differentiation into regulatory T‐cells

“…Activation and differentiation of naive T cells into Tregs is thought to involve signals from tolerogenic DCs and M2 macrophages. Epithelial cells in the cervix and uterus respond to seminal plasma by releasing cytokines, such as GM‐CSF, IL‐1β, IL‐6, and IL‐8, which facilitate the recruitment of neutrophils, macrophages, and DCs, from peripheral blood into the endometrial stroma and epithelium (De et al., 1991 ; Marlin et al 2019 ; Robertson et al., 1996 ). Tolerogenic DCs and M2 macrophages can then be generated in the uterus in response to soluble mediators in seminal plasma, including prostaglandin E (PGE), TLR4 ligands, transforming growth factor‐β (TGF‐β) and other cytokines (Schjenken et al., 2015 ).…”