Abstract
HIV-1 infection is transmitted primarily by sexual exposure, with semen being the principal contaminated fluid. However, HIV-specific immune response in semen has been understudied. We investigated specific parameters of the innate, cellular, and humoral immune response that may affect semen infectivity in macaques infected with SIVmac251. Serial semen levels of cytokines and chemokines, SIV-specific antibodies, neutralization, and FcγR-mediated functions and SIV-specific T-cell responses were assessed and compared to systemic responses across 53 cynomolgus macaques. SIV infection induced an overall inflammatory state in the semen. Several pro-inflammatory molecules correlated with SIV virus levels. Effector CD8+ T cells were expanded in semen upon infection. SIV-specific CD8+ T-cells that expressed multiple effector molecules (IFN-γ+MIP-1β+TNF+/−) were induced in the semen of a subset of SIV-infected macaques, but this did not correlate with local viral control. SIV-specific IgG, commonly capable of engaging the FcγRIIIa receptor, was detected in most semen samples although this positively correlated with seminal viral load. Several inflammatory immune responses in semen develop in the context of higher levels of SIV seminal plasma viremia. These inflammatory immune responses could play a role in viral transmission and should be considered in the development of preventive and prophylactic vaccines.
Highlights
More than 80% of new HIV-1 infections worldwide occur during sexual intercourse, involving mucosal transmission of the virus [1,2,3]
Seminal plasma levels of inflammatory cytokines may have a major impact on shedding of cell-free and cell-associated virus, and they may affect the state of the recipient’s cells in the female reproductive tract (FRT) and rectum, increasing the risk of mucosal HIV-1 transmission. We measured these parameters in seminal plasma samples of macaques intravenously infected with the high dose of 5,000 animal infectious dose 50% (AID50) of SIVmac251 virus to define the relationship between cytokine composition and viral seeding of the male genital tract (MGT)
Blood viral load (BVL) strongly correlated with seminal viral load (SVL) (r = 0.67, p < 0.0001, n = 25, Figure 1A), confirming our previously published results [40], as well as those reported for HIV-1-infected patients [6, 45,46,47]
Summary
More than 80% of new HIV-1 infections worldwide occur during sexual intercourse, involving mucosal transmission of the virus [1,2,3]. Mucosal and genital tract tissues constitute the major source of HIV-1 contaminating fluids. Semen, which contains both cell-free particles and infected cells [4,5,6], represents the main vector of HIV-1 dissemination, illustrated in part by transmission occurring more frequently from men to men and women than women to men [7]. Very little is known about the actors of the innate and HIV-specific adaptive immune response present in semen that may limit or enhance viral transmission. Improved knowledge of the role of antibodies and T cells present in semen may help in the development of more pertinent strategies in the field of HIV-1 transmission prevention
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