The Role of DC-SIGN and DC-SIGNR in HIV and SIV Attachment, Infection, and Transmission

Abstract

Receptor binding largely governs HIV tropism since the presence of CD4 and an appropriate coreceptor, most often CCR5 or CXCR4, is a prerequisite for efficient membrane fusion and human immunodeficiency virus (HIV) infection (Alkhatib et al., 1996; Choe et al., 1996; Deng et al., 1996; Doranz et al., 1996; Dragic et al., 1996; Feng et al., 1996). Binding of the viral envelope (Env) protein to CD4 induces conformational changes in the gp120 subunit of Env that enable it to interact efficiently with a coreceptor (Lapham et al., 1996; Trkola et al., 1996; Wu et al., 1996). CD4 binding may also trigger conformational changes in gp41 that lead to exposure of the fusion peptide (Furuta et al., 1998; Melikyan et al., 2000). While the structural consequences of coreceptor binding are not well understood, it is clear that binding to coreceptor is needed for the final conformational changes in Env that lead to membrane fusion and virus entry. Inhibitors that prevent Env-coreceptor binding or that directly block conformational changes in Env needed for membrane fusion have been developed and are now in clinical trials (Doranz et al., 2001; Kilby et al., 1998). While engagement of CD4 and a coreceptor is required for efficient virus entry, simple attachment of HIV to the cell surface can occur via interactions with other cell surface molecules (reviewed in Ugolini et al., 1999). Attachment can be rate limiting for viral infection as evidenced by the fact that procedures which concentrate virus on the cell surface in vitro, such as spinoculation or inclusion of polycations in the virus inoculum, can markedly improve infection efficiency (O’Doherty et al., 2000). Binding of HIV to cell surface molecules such as heparan sulfate, or the inclusion of cellular adhesion proteins such as CD44, ICAM-1, or CD62L in the viral envelope,