3 CD4: The Receptor for HIV

CD4, the human immunodeficiency virus (HIV) receptor, is a T-cell surface glycoprotein (Reinherz et al. 1979Reinherz et al. 1980). Its normal function is to participate as a coreceptor in the antigen- and class II major histocompatibility complex (MHC)-dependent interactions that initiate T-cell activation (for review, see Janeway et al. 1989). It is believed to form a complex with the T-cell receptor and a peptide-bearing class II molecule, as shown schematically in Figure 1. HIV infection requires CD4 expression, and attachment to CD4 is the initial step in viral entry (Dalgleish et al. 1984; Klatzmann et al. 1984; Maddon et al. 1985). It is likely that CD4 also has a second role—to trigger a conformational change in the HIV envelope glycoprotein and thereby to potentiate the fusion of viral and cellular membranes (Moore et al. 1991; Sattentau et al. 1991). HIV can attach only to CD4 from humans and closely related species (McClure et al. 1987). The extent and essential characteristics of the HIV-binding site on human CD4 have been thoroughly characterized by a combination of structural and mutational studies (Moebius et al. 1992a). The HIV-gp120 side of this contact is less well understood, because a crystal structure of the envelope glycoprotein is still lacking. STRUCTURE OF CD4 The amino acid sequence of CD4, derived from initial cDNA cloning, revealed a 372-residue extracellular domain linked by a hydrophobic transmembrane segment to a 41-residue cytoplasmic tail (Fig. 2) (Maddon et al. 1985). More detailed analysis, based on additional sequences, suggested that the extracellular...