The presence of sexually transmitted diseases (STDs) in women increases susceptibility to sexual transmission of HIV and over 300 million people worldwide are estimated to have STDs. The long-term goal of our research is to develop an animal model of HIV vaginal infection and use it to study how STDs increase susceptibility to HIV infection. The model will also be useful for evaluating the efficacy of microbicides in preventing HIV infection as well as studies of mucosal anti-HIV immunity. The specific goals of this innovation grant application are to develop a murine HIV vaginal infection model using mice transgenic (Tg) for human CD4, CCR5 and cyclin T1 and use the model to determine if a pre-existing infection by herpes simplex virus type-2 (HSV-2) increases susceptibility to subsequent infection by HIV. HSV-2 is an especially appropriate STD to study because it is well-documented to increase susceptibility to HIV infection and it is highly prevalent. In addition, there is an extensive supportive literature on HSV-2 vaginal infection in mice. This proof-of-concept study will establish if the Tg mice can be used as a model for sexual transmission of HIV and if HSV-2 pre-infection increases HIV infection in this model. Mice will be infected with HIV capable of only a single round of infection, which has the advantages of facilitating identification of the initial targets of HIV infection and providing a substantially reduced biohazard. HIV infection will be measured by detection of HIV DNA and appearance of green fluorescence protein-positive cells.
In Aim 1 we will determine if intravaginal infection of Tg mice with HIV results in detectable HIV infection and if a pre-existing HSV-2 infection, either acute or latent, affects susceptibility to HIV infection.
In Aim 2, we will determine the effect of HSV-2 infection on the trafficking of HIV-infected cells to lymphoid tissue and the replication state and phenotype of HIV-infected cells. This revised application includes new data that shows infection of Tg mice by HIV can be detected both in vitro and in vivo thus indicating the feasibility of the proposed experiments.
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