The primary cellular receptor for HIV entry is CD4. However, expression of CD4 on a target cell is necessary but not sufficient for HIV entry and infection. Several chemokine receptors act as co-factors that allow HIV entry when co-expressed with CD4 on a cell surface.

The first of these to be identified was CXCR4, or fusin, which is expressed on T cells (Feng et al., 1996). Co-expression of CXCR4 and CD4 on a cell allow T-tropic HIV isolates to fuse with and infect the cell. HIV gp120 interacts with both CD4 and CXCR4 to adhere to the cell and to effect conformational changes in the gp120/gp41 complex that allow membrane fusion by gp41. CXCR4 is expressed on many T cells, but usually not on macrophages and does not allow fusion by macrophage-tropic (M-tropic) HIV isolates (Feng et al., 1996). It is interesting to note that stimulation with some bacterial cell wall products upregulates CXCR4 expression on macrophages and allows infection by T-tropic strains of HIV (Moriuchi et al., 1998).

Shortly after the identification of CXCR4, another co-receptor was identified. CCR5, which is expressed on macrophages and on some populations of T cells, can also function in concert with CD4 to allow HIV membrane fusion (Deng et al., 1996; Dragic et al., 1996; Alkhatib et al., 1996). HIV gp120 binding to CCR5 is CD4-dependent, as antibody inhibition of CD4 can reduce binding to CCR5 by 87% (Trkola et al., 1996). M-tropic HIV isolates appear to use CCR5 as their co-receptor for infection both of macrophages and of some T cells. Individuals with certain mutations in CCR5 are resistant to HIV infection (Liu et al., 1996; Samson et al., 1996; Dean et al., 1996).

CCR5 and CXCR4 appear to be the two major co-receptors for HIV entry into cells, but they are not the only such chemokine co-receptors. CCR3, a chemokine expressed on eosinophils and microglia, is used by some strains of HIV for infection of the microglia and resulting CNS pathology (He et al., 1997). It is possible that other such chemokine receptors can also bind HIV gp120 and be used for HIV entry.

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