Hepatitis C virus (HCV) coinfection is common in human immunodeficiency virus type I (HIV-1) infected subjects. Epidemiological data suggest that in HIV-1 and HCV coinfected patients, HCV infection is more severe and progression to AIDS is more rapid. Furthermore, HIV infection was reported to facilitate mother-to-infant transmission of HCV and also HCV infection was reported to facilitate mother-to-infant transmission of HIV. Our overall hypothesis is that HCV replicates in lymphoid cells and that this phenomenon is responsible for the observed interactions between HIV-1 and HCV infections. Using strand-specific assays, we have demonstrated the presence of HCV RNA negative strand, which is a viral replicative intermediary, in multiple extrahepatic sites, but particularly common in lymphoid tissue. This infection was mainly localized in monocyte/macrophage cells. Moreover, we found that viral sequences at extrahepatic replication sites commonly differ from circulating and liver-derived sequences. Our proposal aims to further characterize extrahepatic HCV replication among HIV-1-infected subjects. Furthermore, we will analyze the presence of HCV replication in peripheral blood mononuclear cells (PBMCs) and cervical lavage cells in a large group of HIV-1-positive mothers and we will correlate these data with transmission of HCV and HIV-1 into children. To determine whether macrophage-derived HCV strains are responsible for viral transmission into children, we will analyze viral quasispecies composition in serum and PBMCs from mothers and children and in cervical lavage cells from mothers. We will also determine whether HCV infection of antigen presenting cells affects their function. Accordingly, we will culture dendritic cells from HCV-infected and uninfected individuals and compare them in functional assays in vitro. In summary, our studies will further characterize extrahepatic replication of HCV in HIV-1 infected subjects and will elucidate its role in mother-to-infant transmission of these two viruses.
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