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Center for Nonlinear Studies |
During the sexual transmission of HIV, the virus must circumvent mucosal epithelial barriers, which protect underlying CD4 positive target cells. How HIV reaches resident target cells to establish infection is poorly understood. Using fluorescently tagged HIV we have begun to define how the virus interacts with the mucosal barriers. In the female genital tract, we find that HIV can breach both the columnar epithelium of the endocervix and the squamous epithelium of the endocervix utilizing both human tissue explant cultures and the rhesus macaque vaginal transmission model. In the squamous epithelium, the virus enters the epithelium by being adsorbed into the interstitial spaces between the superficial cells. Interestingly, we find that cervical mucus provides a protective role, especially for the columnar epithelium where the cervical mucus is produced. Utilizing these systems we can show that the presence of virus binding antibodies can further slow the transport of HIV through the protective mucus barrier. Further, the addition of the recently identified seminal enhancer of virus infectivity (SEVI) appears to function as an inhibitory factor, decreasing the efficiency of virus entry into the epithelial barrier in contrast to the enhancing effects observed in tissue culture. Having defined how HIV interacts with the mucosal barriers we have extended our analysis to single cycle vector systems, which allows the identification of the target cells infected by the inoculum of the initial virus exposure. Initial studies using this system in the Depo-Provera rhesus macaque sexual transmission model reveal that foci of multiple transduced CD4 T cells can be detected just below the columnar epithelial and within the squamous epithelial barriers of the female macaque genital tract. These observations suggest that the virus initially identified as circumventing the mucosal epithelial barriers can infect resident HIV target cells. Further the identification of foci of transduced (infected) cells suggests that issues with local epithelial barrier integrity may allow regional virus penetration facilitating transmission. An effective vaccine will ideally block transmission by altering virus interaction with and penetration of the mucosal epithelial barriers. A better understanding of the earliest events of sexual transmission should facilitate the development of a vaccine with this ability.
Host: Robert Ecke and Eddy Timmermans, CNLS, 667-1444