Role of DC-SIGN in HIV infection

University Of Texas Hlth Sci Ctr San Ant, San Antonio TX

Investigators

Abstract

Dendritic cells (DCs) are thought to play an important role in the dissemination of HIV-1 and establishment of infection. HIV subverts the normal trafficking process of DCs for its transport from mucosal surfaces to the T cell areas of draining lymphoid tissues. The proficiency of DCs in interacting with T cells makes them prime candidates for initiating and enhancing viral infection. The recent discovery that DC-SIGN, a surface receptor with high expression in DCs promotes efficient HIV infection in trans of cells that express CD4 and chemokine receptors suggests that this molecule might play a key role in DC-HIV interactions. In preliminary studies we demonstrate that plasticity of the DC-SIGN gene (designated here as DC-SIGN1), and another highly homologous gene designated as DC-SIGN2, generates a wide repertoire of DC-SIGN-like molecules. This repertoire includes potentially soluble isoforms as well as a wide array of membrane-bound DC-SIGN-like molecules that differ in their extracellular ligand (gp120) binding domain. We will test the hypothesis that DC-HIV interactions are mediated via a large class of polymorphic, but structurally-similar molecules that are generated by the alternative splicing of two distinct, but highly related genes i.e., DC-SIGN1 (original version) or DC-SIGN2. Three aims will be pursued. Aim #1 will determine the molecular repertoire and cellular distribution of DC-SIGN1 and DC-SIGN2 isoforms. Aim #2 will determine the gp120 adhesivity and HIV-1 trans-infection activity of DC-SIGN1 and DC-SIGN2 isoforms, and elucidate if naturally occurring DC-SIGN1 isoforms lacking the transmembrane domain are soluble inhibitors of HIV-1 binding to DC- SIGN1. To seek genetic evidence for a role of DC-SIGN1 in HIV-1 pathogenesis in vivo, in aim #3 we will determine the association between polymorphisms in DC-SIGN1 and risk of transmission and clinical outcome in large cohorts of HIV-infected and uninfected individuals. Our expectation is that these studies will clarify and further significantly our understanding of the role of DC-SIGN-mediated events in DC-HIV interactions in vitro, and HIV pathogenesis in vivo. They will also provide a springboard for framing new and reframing old problems related to understanding DC-HIV and DC-T cell interactions, events that play key roles in HIV pathogenesis. Our studies also place us in a unique position to pursue strategies to block DC-HIV interactions thought to be necessary for HIV transmission.