This proposal will concentrate on how the intact human placental villous becomes infected with different strains of HIV. Whether there is a differential ability of syncytial-inducing and non-syncytial-inducing HIV strains to infect the placenta during the first/third trimesters will be determined. Specific infection of placental cell types - syncytiotrophoblast, cytotrophoblast, stromal, endothelial, and Hofbauer cells - will be determined by in situ PCR/hybridization. A model that simulates cellular conditions as noted in utero and allows definition of the nature and localization of the HIV infection and viral infectivity for placentae from the first/third trimesters will be used. How anti-HIV therapy either alone or in combination can reduce the infectivity of the non-in utero infected placentae will be resolved, while examining if there is any significant cellular/placental toxicity being produced by the mono/multiple therapy. How the in utero infected placentae responds to anti-HIV therapy in vitro will be determined. Two placental populations will be studied. a) Infected placentae from mothers who are currently receiving anti-HIV therapy. In these placentae, which multiple anti-HIV therapy benefit the fetus in reducing the infection of the placenta and transmission of HIV to the fetus will be established. The in vitro data will be correlated with the clinical information. b) The infected placentae from HIV-positive mothers, who have never been treated during pregnancy with any anti-HIV therapy, will be evaluated for mono/multiple therapy concurrently and compared with those placentae treated in utero. The pharmaco-kinetics/toxicity of mono/multiple anti-HIV therapy will be examined under extended (16-24 hr) dual human term placental perfusion conditions in a multiple-dosing manner. It is anticipated that these studies will establish how different HIV strains infect the human placenta from different gestational ages, which placental cells are being infected, and establish how mono/multiple anti-HIV therapy can be metabolized/ transported and reduce the HIV infection in the human placenta.
