Worldwide, more than 80% of new infections by the human immunodeficiency virus type 1 (HIV-1)a occur via mucous membrane transmission during sexual intercourse. The genital tract mucosa is the main source of fluids contaminated with HIV-1. Semen, which contains both infected cells and cell-free viral particles, is the main vector for HIV-1 diffusion, an aspect illustrated by the greater frequency of male-to-male or male-to-female transmission compared to female-to-male transmission. HIV-1 transmission correlates with seminal viral load and infection stage, but the mechanisms driving it are not completely understood. To achieve infection through the genital mucosa, the semen-borne HIV-1 must surmount major immunological and physiological obstacles to pass the epithelium and reach the underlying target cells.
A number of factors affecting semen infectivity and the risk of transmitting HIV-1 to a partner have been identified, but little is known on the specifics of innate and adaptive immune responses to HIV-1 in the semen and how they may limit or favor viral transmission. Indeed, must studies to date on immune responses to HIV-1 in the genital tract have focused on women; those looking at the male genital tract remain limited. Better knowledge on the roles of the antibodies and the T lymphocytes in semen could contribute to the elaboration of more pertinent prevention strategies.
In pursuit of that goal, a team from the Infectious Disease Models and Innovative Therapies division (UMR1184/ImVa) led a study, published in Frontiers in Immunology, on the innate and adaptive immune responses in semen. They used SIVbmac251-infected macaques, the most pertinent simian model for human HIV-1 infection.
The team analyzed immune dynamics in seminal plasma, including viral load, inflammatory cytokine levels, anti-SIV antibody responses and T lymphocyte (CD8+) levels during acute and chronic infection.
The researchers showed that SIV infection provokes a global inflammatory state in the seminal plasma. In the infected macaques and during primary infection, several pro-inflammatory (IL-8, IL-15, IL-18, IFN-γ, IP-10 CCR5) and immunomodulatory (IL-13) molecules were present at high rates, compared to the levels observed in uninfected macaques. That inflammatory environment appears to enable the recruitment of target cells and the modulation of immune cell activation. An experimental demonstration was made by showing high levels of preexisting, active CD8+ T lymphocytes also positive for the CD69 receptor in the male genital tract, and an increase in those levels during SIV infection.
The team also observed a significant increase in CD8+ T lymphocytes also positive for the CCR5 and CXCR3 chemokine receptors, a phenomenon typical of the Tc1 phenotype, and coherent with the ability of these cells to migrate to inflammatory tissues.
In most of the infected primates, the researchers found antibodies able to engage the FcγRIIIa receptor. The presence of those antibodies suggests an antibody-dependent cell-mediated cytotoxicity effect. Of note: FcγRIIIa binding in semen was positively correlated with SIV-specific antibody titers and seminal viral load.
The study thus suggests that an inability to control viral replication in the semen of SIV-infected macaques may be related to general inflammation and immune activation. All leads to think that these same processes in human semen and the male genital tract could contribute to increased HIV-1 transmission. The IDMIT team's work sheds light on the complex interactions between inflammation and immune activation and the role they may play in the modulation of semen infectivity and transmission risks. These new insights on the regulation of immunity in the male genital tract may contribute to improving the efficacy of current preventative measures and identifying novel critical factors in HIV-1 transmission.
a : There are two strains of human immunodeficiency virus, HIV-1 and HIV-2.
They share 42% homology, but HIV-1 is more frequently encountered. HIV-1 is
further divided into groups, and in the largest of those groups (group M) into
subtypes, of which there are nine. These subtypes tend to be distributed
geographically. For example, subtype B is most frequently encountered in North
America and Europe. HIV-1 may be transmitted through sexual, blood exposure or
maternal-fetal routes.
b : simian immunodeficiency virus