Our previous work has shown that entry of HIV-1 into cells expressing CD4 and CCR5 is substantially dependent on sulfated tyrosines at the amino terminus of CCR5. Sulfated tyrosines also contribute to the association of MIP-1 c about and RANTES with CCR5. Motifs consistent with tyrosine sulfation are observed on most chemokine receptors and on all receptors identified to date that can serve in vitro as HIV-1 or SIV coreceptors. Here I seek to (1) further characterize the role of tyrosine sulfation of CXCR4 and CCR3 in supporting the entry of HIV-1 isolates that can utilize these receptors (2) describe the relative importance of the two known tyrosyl sulfotransferases in sulfating CCR5, their preferred motifs, and the implications of their differential tissue distribution in HIV-1 target cells (3) further characterize the ability of tyrosine-sulfated peptide derivatives of CCR5 to inhibit HIV-1 entry and bind HIV-1 envelope glycoproteins, in order to define determinants on CCR5 and on HIV-1 envelope glycoprotein necessary for their interaction, and to test a multi-step model of HIV-1 entry. These studies will describe an association critical to the entry of HIV-1 into its target cells that may be usefully targeted by small molecule inhibitors, perhaps especially by small sulfated compounds that mimic the N-terminal domain of CCR5.