Heterosexual transmission of human immunodeficiency virus (HIV) infection occurs through mucosal surfaces and is the major route of infection worldwide. This mode of transmission is increasing in prevalence more rapidly than any other in the West (31
). Male-female transmission rates (per contact infectivity estimated to be 0.0009 in North American women) are reported to be approximately eight times more efficient than female-male rates, with history of concomitant sexually transmitted diseases (STDs) being the most strongly associated risk factor (22
). Conflicting data have been reported on the selective pressure of mucosal transmission on the phenotypic and genotypic characteristics of transmitted viral isolates from a heterogeneous inoculum. Predominant isolation from peripheral blood of virus able to infect both macrophages and CD4+
T lymphocytes (non-syncytium inducing [NSI], M-tropic) over those that preferentially infect T lymphocytes (syncytium inducing [SI], T-tropic), during or near to acute HIV infection have lead to the suggestion that NSI viruses may be more readily transmitted via mucosal routes (40
). The mechanisms for such selective transmission of HIV isolates may be one of either selective penetration or selective amplification within the infected host (33
). Analyses of genital biopsies from HIV-infected women and preliminary studies from this laboratory, using cervical organ culture as a model of primary infection, have demonstrated that HIV-infected cells reside within subepithelial mucosa, with no evidence of HIV infection of epithelial cells (20
). Furthermore, it has been demonstrated that the primary targets of simian immunodeficiency virus (SIV) infection, following intravaginal infection of macaques, are cervical and vaginal subepithelial cells (35
). Such data indicate that establishment of HIV infection requires transepithelial penetration. Whether intact genital epithelium presents a barrier to, or is an active participant in, HIV transmission has not been tested in primary human mucosal tissue.
Epithelium along the female genital tract differs in structural cellular organization: the vagina and ectocervix, the site most exposed to a natural inoculum, are composed of stratified epithelium, whereas the endocervix is composed of a single epithelial monolayer. Multiple mechanisms for HIV transmission across genital epithelia have been proposed: direct HIV infection of epithelial cells, transcytosis of HIV through epithelial cells, epithelial transmigration of HIV-infected donor cells, uptake of HIV by intraepithelial Langerhans cells, or circumvention of epithelium via breaches in epithelial integrity (14
). Evidence for HIV infection of, or transcytosis through, epithelial cells is derived from in vitro studies using epithelial cell lines, which may bear little relation to primary intact genital epithelium (1
). Furthermore, infection or transcytosis in such models is dependent on cell-associated virus, an observation at odds with efficient mucosal cell-free SIV or feline immunodeficiency virus infection (3
). Strong epidemiological association of inflammatory ulcerative venereal disease with HIV transmission and observation that mucosal SIV transmission may be enhanced following thinning of vaginal epithelium by progesterone implants suggests a barrier role for genital epithelium (18
). Furthermore, recent studies have demonstrated that STDs increase both the number of CD4 cells in genital mucosa and the expression of chemokine receptors known to function as HIV coreceptors, thereby increasing the number of target cells (16
). While HIV may achieve transepithelial penetration by more than one mechanism, the relatively low incidence of per-contact infectivity suggests that this is unlikely to reflect a constitutive mechanism. However, male-female transmission is also influenced by factors relating to the male partner, including seminal viral load and incidence of STDs (31
), all of which have an impact on contact infectivity.
While condoms provide an effective barrier against transmission of HIV and other STDs, they require the consent of the male partner, which cannot always be negotiated by women at risk for infection. Thus, there is an urgent need to develop prevention strategies that are under the personal control of women. The potential of effective topical vaginal virucides to prevent sexual transmission of HIV and other STDs is widely recognized (8
). However, proper evaluation of the efficacy of such agents in blocking HIV infection of female genital tissue has been hampered by the lack of appropriate experimental models.
Thus, understanding the first critical events in genital mucosal transmission of HIV infection is important in developing strategies to block or limit such transmission. In this study, human genital mucosal tissue from premenopausal seronegative women was been used to define primary target cells for HIV infection within genital mucosa, differential susceptibility of such tissue to M-tropic and T-tropic HIV isolates, and the interaction of HIV with genital epithelium. Furthermore, this in vitro model has been used to determine the efficacy of potential vaginal virucides designed to protect women from HIV infection.