Our broad, long-term objective is to prevent HIV infection by changing the genital tract milieu to one that decreases the risk of HIV infection. Since a major route of HIV transmission is between heterosexual partners, a promising HIV-prevention approach is to topically modify the biology and immunology of the female genital tract. First, this may avoid both therapeutic (e.g. compartmentalization, toxicity) and economic problems with current, systemic, treatments of HIV. Second, the immunology of the female genital tract is modifiable (e.g., topical vaccines have been used successfully in animal models of HIV and HSV). Third, our laboratory is particularly well-qualified to investigate key HIV-related modifications in the immunology and virology of the female genital tract including susceptibility to HIV infection and expression of HIV receptors such as chemokine receptors. Fourth, our laboratory has established and used over the last two years a cervical-vaginal explant tissue model that is well-tolerated, reproducible, and predictable. Based on over 130 cervical-vaginal biopsies performed over the last two years, we have described a direct correlation between the expression of individual chemokine receptors and infection by HIV-1 isolates using those specific receptors. Hypothesis: HIV infection through heterosexual transmission can be prevented by decreasing the ability of chemokine receptors on host immune cells in the female genital tract to function as HIV co-receptors (decreased virion binding). Two clinical (Aims number 1,2) and one explant culture (Aim number 3) conditions will be tested in which chemokine receptor expression is altered to see if susceptibility to HIV infection is altered in parallel.
Aims : [l] Are clinical treatment successes that eradicate STDs associated with decreases in both chemokine receptor expression in their genital tract and in the susceptibility of these tissues to HIV infection? If yes, then improved screening, early diagnosis and aggressive therapy of STDs might help prevent HIV dissemination in populations. [2] Do variations in progesterone levels during the menstrual cycle cause parallel shifts in chemokine receptor expression and in susceptibility to HIV infections? A strong correlation would suggest a rationale for developing practical, hormonal therapy to decrease susceptibility to HIV infection. [3] Does altering chemokine receptor expression in explant cultures of female genital tract tissues, by exposing these tissues to agents that modify chemokine receptor expression (by different mechanisms), change their susceptibility to HIV infection (measured as the HIV DNA of infected tissues). Agents include: IL-10, AOP-RANTES, and AMD3100, all agents known to alter the ability of chemokine receptors to function as HIV co-receptors. Hypothesis confirmation will constitute a rationale for a clinical trial of these or similar agents applied topically, in vivo, to the female genital tract.
