Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of versus Models.

Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggest that CCR5 CD4 T cells are initial targets for HIV-1 infection, the impact of semen on T cell CCR5 expression and ligand production remains inconclusive. To determine if semen modulates the lymphocyte CCR5 receptor/ligand axis, primary human T cell CCR5 expression and natural killer (NK) cell anti-HIV-1 antibody-dependent beta chemokine production was assessed following seminal plasma (SP) exposure. Purified T cells produce sufficient quantities of RANTES to result in a significant decline in CCR5 T cell frequency following 16 h of SP exposure ( = 0.03). Meanwhile, NK cells retain the capacity to produce limited amounts of MIP-1α/MIP-1β in response to anti-HIV-1 antibody-dependent stimulation (median, 9.5% MIP-1α and/or MIP-1β), despite the immunosuppressive nature of SP. Although these experiments suggest that SP-induced CCR5 ligand production results in the loss of surface CCR5 expression on CD4 T cells, the implications are unclear. We therefore vaginally exposed five pigtail macaques to SP and found that such exposure resulted in an increase in CCR5 HIV-1 target cells in three of the animals. The data support a growing body of evidence suggesting that semen exposure recruits target cells to the vagina that are highly susceptible to HIV-1 infection, which has important implications for HIV-1 transmission and vaccine design. The majority of HIV-1 vaccine studies do not take into consideration the impact that semen exposure might have on the mucosal immune system. In this study, we demonstrate that seminal plasma (SP) exposure can alter CCR5 expression on T cells. Importantly, studies of T cells in culture cannot replicate the conditions under which immune cells might be recruited to the genital mucosa , leading to potentially erroneous conclusions about the impact of semen on mucosal HIV-1 susceptibility.