124 Male-to-Female HIV-1 Transmission: Lessons from Ex Vivo

The mechanisms of male-to-female HIV-1 transmission mediated by semen are not well-understood. To decipher these mechanisms, we developed a system of cervico-vaginal tissue ex vivo to which HIV-1 is transmitted from semen under controlled laboratory conditions. Semen samples obtained from HIV-1-infected and control men were analyzed for the presence of 21 cytokines, and HIV-1 transmission was simulated ex vivo by deposition on cervico-vaginal explants of virus suspended in semen or in PBS enriched with particular cytokines. In HIV-1-infected men, the cytokine spectrum was significantly changed, resulting in the establishment of new correlations and the strengthening of pre-existing correlations between different cytokines: HIV-1 infection increases the number of such correlations from 21 to 72. These changes in semen were local and different from ones in blood from the same individuals. One of the most upregulated seminal cytokines was IL-7, which enhanced replication of HIV-1 in cervico-vaginal tissue. This enhancement was associated with the suppression of apoptosis as evaluated from the expression of apoptotic markers, a decrease in the depletion of infected cells as evaluated from flow cytometry, and an increase in cell cycling as evaluated from Ki67 staining. In conclusion, HIV-1 establishes new strong correlations between various cytokines, thus imposing a high rigidity on their network that may contribute to the impaired capacity of the immune system to respond to microbial challenges. Seminal cytokines, in particular IL-7, may be key determinants of HIV-1 transmission from men to their uninfected female partners through vaginal intercourse and may become a new target for preventive and therapeutic strategies.