Search

In this thesis we aimed to better understand the cellular and molecular mechanism underlying selective transmission of HIV-1 by dendritic cells (DCs). During sexual contact a number of different HIV-1 variants are present in vaginal tract. However, only one or a few HIV-1 variants are transmitted with the specific phenotypical characteristics. Langerhans cells (LCs) are the first component of the immune system that can encounter viruses. We have investigated whether LCs are a selective barrier that restrict transmission of specific HIV-1 variants and if so, what are the viral factors as well as host factors underlying this selection. We have shown that both LCs and sub-epithelial DCs play a role in the selection of wild-type over drug resistant variants through a viral fitness dependent mechanism. Our data revealed that LCs selectively transmit R5-HIV-1 variants, however, this selection is not attributed to the viral fitness but is through an LC-intrinsic inhibitory mechanism. We also investigated the molecular mechanism underlying antiviral activity of LCs. Our data revealed that human TRIM5α is a potent restriction factor in LCs for HIV-1. This restriction is dependent to Langerin binding to HIV-1, which directs the virus into a TRIM5α-mediated autophagy degradative pathway. Our data also showed that activation of LCs as well as infection with HIV-1 facilitated the transmission of HCV by LCs through trans pathway. Increased knowledge of the mechanism underlying transmission of viruses using primary cells and ex vivo models is anticipated to provide novel targets and methods to prevent and treat viral infections.