Semen protects CD4⁺ target cells from HIV infection but promotes the preferential transmission of R5 tropic HIV

Sexual intercourse is the major means of HIV transmission, yet the impact of semen on HIV infection of CD4⁺ T cells remains unclear. To resolve this conundrum, we measured CD4⁺ target cell infection with X4 tropic HIV IIIB and HC4 and R5 tropic HIV BaL and SF162 after incubation with centrifuged seminal plasma (SP) from HIV-negative donors and assessed the impact of SP on critical determinants of target cell susceptibility to HIV infection. We found that SP potently protects CD4⁺ T cells from infection with X4 and R5 tropic HIV in a dose-and time-dependent manner. SP caused a diminution in CD4⁺ T cell surface expression of the HIVR CD4 and enhanced surface expression of the HIV coreceptor CCR5. Consequently, SP protected CD4⁺ T cells from infection with R5 tropic HIV less potently than it protected CD4⁺ T cells from infection with X4 tropic HIV. SP also reduced CD4⁺ T cell activation and proliferation, and the magnitude of SP-mediated suppression of target cell CD4 expression, activation, and proliferation correlated closely with the magnitude of the protection of CD4⁺ T cells from infection with HIV. Taken together, these data show that semen protects CD4⁺ T cells from HIV infection by restricting critical determinants of CD4⁺ target cell susceptibility to HIV infection. Further, semen contributes to the selective transmission of R5 tropic HIV to CD4⁺ target cells.