UTILIZATION OF CHEMOKINE RECEPTORS, ORPHAN RECEPTORS, AND HERPESVIRUS-ENCODED RECEPTORS BY DIVERSE HUMAN AND SIMIAN IMMUNODEFICIENCY VIRUSES

Human immunodeficiency virus type 1 (HIV-1) requires both CD4 and a co receptor to infect cells. Macrophage-tropic (M-tropic) HIV-1 strains u tilize the chemokine receptor CCR5 in conjunction with CD4 to infect c ells, while T-cell-tropic (T-tropic) strains generally utilize CXCR4 a s a coreceptor. Some viruses can use both CCR5 and CXCR4 for virus ent ry (i.e., are dual-tropic), while other chemokine receptors can be use d by a subset of virus strains. Due to the genetic diversity of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) and the potential for chemokine receptors other than CCR5 or CXCR4 to influence viral pathog enesis, we tested a panel of 28 HIV-1, HIV-2, and SIV envelope (Env) p roteins for the ability to utilize chemokine receptors, orphan recepto rs, and herpesvirus-encoded chemokine receptor homologs by membrane fu sion and virus infection assays. While all Env proteins used either CC R5 or CXCR4 or both, several also used CCR3. Use of CCR3 was strongly dependent on its surface expression levels, with a larger number of vi ral Env proteins being able to utilize this coreceptor at the higher l evels of surface expression. ChemR1, an orphan receptor recently shown to bind the CC chemokine I309 (and therefore renamed CCR8), was expre ssed in monocyte and lymphocyte cell populations and functioned as a c oreceptor for diverse HIV-1, HIV-2, and SIV Env proteins. Use of ChemR 1/CCR8 by SIV strains was dependent in part on V3 loop sequences. The orphan receptor V28 supported Env-mediated cell-cell fusion by four T- or dual-tropic HIV-1 and HIV-2 strains. Three additional orphan recept ors failed to function for any of the 28 Env proteins tested. Likewise , five of six seven-transmembrane-domain receptors encoded by herpesvi ruses did not support Env-mediated membrane fusion. However, the chemo kine receptor US28, encoded by cytomegalovirus, did support inefficien t infection by two HIV-1 strains. These findings indicate that additio nal chemokine receptors can function as HIV and SIV coreceptors and th at surface expression levels can strongly influence coreceptor use.