The human immunodeficiency virus Type 1 (HIV-1) rep- despite apparently normal CD4 processing and expression (Ashorn et al., 1990; Clapham et al., 1991; Maddon resents a significant pathologic adversary. Despite the limited size of its genome, this virus encodes an array et al., 1986). This species restriction is at the level of virus entry and can be rescued by the formation of polykaryons of proteins that confer a wide repertoire of pathogenic mechanisms to sustain infection, including the ability to between human and nonhuman cells, indicating that nonhuman cells lack an appropriate cofactor or coreceptor escape the immunologic defenses of the host (Fauci, 1996; Pantaleo et al., 1993). This highlights the impor- required for virus infection (Broder et al., 1993; Dragic et al., 1992). Further evidence that CD4 alone is not suffitance of targeting early events in virus transmission and entry into cells in order to prevent infection and the devel- cient to support virus entry comes from observations that HIV-1 strains exhibit distinct cellular tropisms (Chengopment of the acquired immunodeficiency syndrome (AIDS). Dramatic advances made in the past year have Mayer et al., 1988; Fauci, 1996; Fenyö et al., 1988). Macrophage tropic (M-tropic) strains of HIV-1 fail to enter transidentified certain chemokine receptors as being critical for virus infection in vivo and in vitro, making it possible formed CD4-positive T-cell lines, while T-cell tropic (T-tropic) strainsgenerallyfailtoentermacrophages. These to study the initial events in virus infection in much greater detail. These molecules represent important new differences in cellular tropism suggested that M-tropic strains of HIV might use one coreceptor, while T-tropic targets for anti-viral strategies and afford new opportunities to study HIV-1 pathogenesis at the molecular level. strains might use another (Alkhatib et al., 1996a). While a number of molecules were proposed as HIV-1 corecep-The clinical and laboratory manifestations of immunodeficiency and decreased T-helper cells, which express tors over the years, none proved to be required for infection. Only recently have the bona fide HIV-1 coreceptors the CD4 antigen, led to the identification of this cell surface protein as the primary receptor for HIV-1, HIV-2, and been identified. Their discovery was the consequence of two seminal studies; one which demonstrated that cersimian immunodeficiency virus (SIV). The first evidence that implicated CD4 as the HIV-1 receptor was the ability tain chemokines secreted by CD8/cells have anti-viral activity (Cocchi et al., 1995) and one that identified the of anti-CD4 monoclonal antibodies to inhibit virus infection (Dalgleish et al., 1984; Klatzman et al., 1984). Subse- first HIV-1 coreceptor (Feng et al., 1996). quent studies showed that a bimolecular complex be-Anti-viral activity of CC-chemokines tween CD4 and the viral envelope protein (env) could be immunoprecipitated from infected cells (McDougal et al., Cytotoxic/suppressor CD8/T-lymphocytes have been 1986) and that the induction of CD4 expression rendered shown to suppress HIV-1 production without detectable noninfectable cells sensitive to HIV-1 infection (Maddon alterations in the proliferation and activation of CD4/et al., 1986). However, expression of CD4 in nonhuman target cells (Walker et al., 1986). This activity was demoncells (and some human cell lines (Chesebro et al., 1990)) strated to be, at least in part, the result of a novel soluble is not sufficient to confer sensitivity to HIV-1 infection factor that inhibits infection by HIV-1, HIV-2, and SIV