Grant: Operating Grant

Clinical studies show that women are more susceptible to HIV-1 infection compared to men; but the reason for this difference is not well understood. HIV is transmitted in women primarily through sexual transmission, therefore it seems logical that in order to understand why women are more susceptible to this infection, we should try to understand the exact events that take place in the female genital tract leading up to establishment of HIV infection. Our recent studies have shown that when HIV causes inflammatory changes in the female genital tract leading to disruption of the mucosal barrier that is the body's primary defense against entry of HIV . We found that this breach in the mucosal leads to leaking of both HIV as well as other bacteria across the epithelium. This could allow HIV to establish infection as well as cause chronic inflammation that is seen in HIV-infected individuals. With this knowledge, we recently tried to determine if treatment with immune factors, such as IL-22 cytokine that is known for its anti-inflammatory function in the intestine tract, could prevent disruption of mucosal barrier by HIV-1 in the female genital tract. Indeed, we found that if genital epithelial cells were treated with IL-22, they became resistant to inflammatory changes caused by HIV. In the current proposal, we propose to understand the underlying mechanism of how the mucosal barrier is disrupted by inflammatory factors and protected by IL-22 and to test in a humanized mouse whether this can be used as a prophylactic treatment to prevent HIV infection. This research will inform strategies to prevent HIV infection in women, in particular those who are at higher risk for HIV infection, such as women who have unprotected sex, immigrant African-Caribbean and Aboriginal women who have higher biological risk