The role of chemokine receptors in HIV infection across the placenta The main hypothesis of this proposal is that substances (cytokines, chemokines) suppress HIV-co-receptor expression in placenta cells. Despite the progress in preventing HIV-1 infection in children with prenatal ZDV treatment, the mechanism by which the virus penetrates the placental barrier and enters the fetal circulation is not clear. It has been shown that placental that placental macrophages (Hofbauer cells, HF) are susceptible cell free HIV while trophoblasts are susceptible only to transfected virus. We found that HF cells are less susceptible than monocyte derived macrophages (MDM) to infection with HIV-BaL, an R5 virus. Both trophoblasts and Hofbauer cells produce cytokines. Through the proposed experiments, we will investigate the mechanisms of increased resistance to HIV by HF cells and elucidate the specific mechanisms that limit HIV entry in placenta cells.
The specific aims of this period are: 1) To determine the in vivo HIV co-receptor and chemokine expression Hofbauer cells by immunohistochemistry on frozen term placenta sections. 2) To determine chemokine receptor expression (CXCR4, CC45, CCR3, and STRL33) in Hofbauer cells and Trophoblasts by immunofluorescence and 2-color cytofluorometry. 3) To determine the susceptibility of Hofbauer cells to HIV variants derived from vertical transmission. 4) To determine the effect of trophoblast and Hofbauer cells supernatants on HIV replication by PBMC and MDM. The in vitro HIV infection of Hofbauer cells will be conducted using primary isolates characterized for co-receptor utilization and derived from vertical transmission. Four of these viruses have been isolated from transmitter and non-transmitted mothers in Puerto Rico. Additional variants will be obtained from the NIH AIDS Reagent Program in order to identify viral isolates with distinct co-receptor usage. This study will elucidate the viral and host determinants associated with resistance of the placenta to vertical transmission.
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