The genital tract immune milieu: an important determinant of HIV susceptibility and secondary transmission

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Abstract

HIV is generally sexually acquired across the genital or rectal mucosa after exposure to the genital secretions of an HIV-infected partner. Most exposures to HIV do not result in infection, likely due to protection afforded by an intact mucosal epithelium, as well as by innate and adaptive mucosal immune factors present in the genital tract. Another important mucosal determinant of transmission may be the number and activation status of potential HIV target cells, including CCR5/CD4+ T cells and DC-SIGN+ dendritic cells. The simultaneous presence of other genital infections, including classical sexually transmitted infections (STIs), can enhance HIV susceptibility either by breaching the epithelial barrier, recruiting HIV target cells to the genital tract, or by generating a pro-inflammatory local immune milieu. In HIV-infected individuals, genital co-infections increase HIV levels in the genital secretions, thereby increasing secondary sexual transmission. Co-infections that act as important HIV cofactors include human cytomegalovirus (CMV), Herpes simplex virus type 2 (HSV2), Neisseria gonorrhoeae and many others. Strategies focused on genital co-infections, such as vaccines, microbicides and suppressive therapy, are feasible in the short term and have the potential to curb the pandemic.

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Background

The clinical syndrome of AIDS was first recognized over 20 years ago and the discovery of HIV-1 (HIV), the causative virus, followed soon after (Gallo et al., 1983). Since then, more than 25 million people have died of AIDS and an additional 40 million are currently infected by HIV (WHO and UNAIDS, 2004). Despite intense research, no clinically successful HIV vaccines or immunotherapeutics have been developed to date, due in part to the complex interaction between the virus and the host immune

Blood HIV viral load is an important predictor of HIV levels in genital secretions

The first, necessary step in HIV sexual transmission is the shedding of infectious HIV in the genital secretions of an infected person. The most robust predictor of HIV sexual transmission within HIV serodiscordant couples is the level of plasma HIV RNA viremia in the infected partner (Quinn et al., 2000). This probably does not reflect direct contact with blood during sex, but rather that the amount of HIV RNA and/or DNA in genital secretions correlates broadly with the plasma viral load (

Compartmentalized immune factors influence genital HIV shedding

The amount of virus in the genital secretions of an infected person, while quite variable, is on average at least 10-fold less than in the blood (Sheth et al., 2004, Sheth et al., 2005). Mucosal ulceration is associated with higher genital HIV levels (Kreiss et al., 1989), suggesting that the mucosal immune barrier may be important in reducing secondary sexual transmission from an infected person. Although unproven, lower levels of HIV in genital secretions compared to blood may therefore

The effect of antiretroviral therapy on HIV shedding and transmission

Antiretroviral therapy (ART), if prescribed and taken appropriately, is associated with dramatic reductions in blood HIV RNA load, often to undetectable levels. The same effect is seen in the genital tract and it seems likely that ART-induced reductions in both blood and genital tract HIV levels will translate into reduced sexual transmission to sexual partner(s) (Montaner et al., 2006), although this remains to be clinically proven. However, in our own studies, genital HIV RNA shedding was

HIV susceptibility in the female genital tract

After shedding in genital secretions, HIV must cross the mucosal epithelium of the uninfected partner and establish persistent infection. The virus is extremely vulnerable during this time, reflecting the inhospitable environment of the genital tract, the fragility of HIV and the relative paucity of HIV-susceptible target cells in the genital mucosa (Haase, 2005). There are several potential HIV target cell populations in the female genital tract, but productive infection likely involves either

Protective mucosal immunity in the female genital tract

The most effective protection against HIV acquisition is probably an intact genital epithelium (Coombs et al., 2003). This is certainly true for the stratified squamous lining of the vaginal vault, although it is likely that the single cell columnar epithelium of the cervix provides a less robust barrier. In addition to the epithelial barrier, environmental barriers to HIV infection are provided also by the acidic pH of the vagina, by hydrogen peroxide produced by lactobacilli and by

Population dynamics of HIV transmission

A detailed description of HIV transmission dynamics is beyond the scope of this review, but several aspects merit highlighting. The potential for epidemic spread of HIV can be expressed as the magnitude of the basic reproductive rate (R0), where interacting variables are the probability that an individual will infect their sexual partner over the course of a relationship (β), the average number of new sexual partners per unit time (c) and the duration of infectiousness (D), such that R0 = βcD (

The effect of genital co-infections on HIV shedding and sexual transmission

Both sexually transmitted infections (STIs) and other genital infections have been associated with increased HIV genital shedding and, by extension with increased sexual transmission of HIV, as well as with increased HIV susceptibility (Corbett et al., 2002, Kaul et al., 2000a). Such infections may include cytomegalovirus, gonorrhea, chancroid, syphilis, genital herpes, bacterial vaginosis, candidiasis and many others. The identification of key genital infections that enhance HIV sexual

Summary

HIV is shed from mucosal surfaces in an HIV-infected individual and it is at mucosal surfaces that initial HIV exposure occurs in their sexual partners. Therefore, the immune milieu at the mucosal surfaces of both the HIV-infected and susceptible partner is a critical determinant of HIV transmission. HIV is very vulnerable at a mucosal level during the transmission process, as evidenced by the fact that less than 1% of unprotected sexual exposures results in productive HIV infection. A

Acknowledgements

Grant supported by Canadian Institutes of Health Research (RK), Ontario HIV Treatment Network (RK, PS and SW), Canadian Network for Vaccines and Immunotherapeutics (RK), amfAR (RK) and Canada Research Chair Programme (RK).

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