HIV and SIV gp120 binding does not predict coreceptor function.

Interaction of HIV and SIV Envelope (Env) proteins with viral coreceptors is a critical step in viral entry. By using a sensitive and specific gp120 binding assay, we have identified a discordance between the ability of a coreceptor to support Env-mediated membrane fusion and high-affinity binding of gp120. Direct binding of gp120 from the dual-tropic HIV-1 strain 89.6 was not detectable for any coreceptor that it uses for fusion, while detectable binding of gp120s from the R5 HIV-1 strains JRFL and CM235 and the SIV strain 239 was not measurable for many CCR5 chimeras and mutants that function efficiently as viral coreceptors. In comparison, binding of chemokines to these same mutants was highly predictive of their ability to signal. Thus, gp120 is more sensitive than chemokines to perturbations of CCR5 structure. We conclude that while chemokine binding to CCR5 is a good predictor of chemokine receptor function, gp120 binding does not always predict coreceptor function.

Baik SS ，Doms RW ，Doranz BJ 《VIROLOGY》

Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor.

Weissman D ，Rabin RL ，Arthos J ，Rubbert A ，Dybul M ，Swofford R ，Venkatesan S ，Farber JM ，Fauci AS ... -  《NATURE》

Use of GPR1, GPR15, and STRL33 as coreceptors by diverse human immunodeficiency virus type 1 and simian immunodeficiency virus envelope proteins.

Human and simian immunodeficiency viruses (HIV and SIV, respectively) use chemokine receptors as coreceptors along with CD4 to mediate viral entry. Several orphan receptors, including GPR1, GPR15, and STRL33, can also serve as coreceptors for a more limited number of HIV and SIV isolates. We investigated whether these orphan receptors could function as efficient coreceptors for a diverse group of HIV and SIV envelopes (Envs) in comparison with the principal coreceptors CCR5 and CXCR4. We found that a limited number of HIV-1 isolates could mediate inefficient cell-cell fusion with the orphan receptors relative to CCR5 and CXCR4; however, none of the orphan receptors tested could support pseudotype virus infection despite robust infection via CCR5 or CXCR4. All except one of the SIV Envs tested mediated some degree of cell-cell fusion and pseudotype infection, with target cells expressing at least one of these orphan receptors, although CCR5 proved to be the most efficient coreceptor for infection. Only one SIV Env protein, BK28, could mediate infection using GPR1 as a coreceptor, albeit much less efficiently than with CCR5. In addition, use of these coreceptors did not correlate with the published tropism of the SIV clones and was strictly CD4 dependent for both SIV and HIV. We also examined the expression of these molecules in cell lines and primary cells widely used for virus propagation and as targets for infection. All cells examined expressed STRL33, a more limited number expressed GPR15, and GPR1 was much more restricted in its expression pattern. Taken together, our results indicate that GPR15 and STRL33 are rarely used by HIV-1 but are more frequently used by SIV strains, although not in a manner that correlates with SIV tropism.

Edinger AL ，Hoffman TL ，Sharron M ，Lee B ，O'Dowd B ，Doms RW ... -  《VIROLOGY》

HIV-1 coreceptor activity of CCR5 and its inhibition by chemokines: independence from G protein signaling and importance of coreceptor downmodulation.

Alkhatib G ，Locati M ，Kennedy PE ，Murphy PM ，Berger EA ... -  《VIROLOGY》

Interactions of CCR5 and CXCR4 with CD4 and gp120 in human blood monocyte-derived dendritic cells.

Dendritic cells (DC) and macrophages play an important role in the generation of immune responses and transmission of HIV infection. It has been recently found that, in the presence of gp120, CD4 can be efficiently coimmunoprecipitated by anti-CXCR4 antibodies from lymphocytes and monocytes but not from blood monocyte-derived macrophages. The gp120-CD4-CXCR4 complex formation paralleled the ability for these cell types to support X4 (LAV) HIV-1 envelope glycoprotein (Env)-mediated fusion. Here we report that, unlike macrophages but similar to lymphocytes and monocytes, human blood monocyte-derived DC allow efficient complex formation among the HIV-1 coreceptor CXCR4, the primary receptor CD4, and the Env gp120 (LAV) which parallels their fusion ability with cells expressing HIV-1 Env (LAV). In addition, DC behaved similarly to macrophages, lymphocytes, and monocytes in their ability to support formation of complexes between CD4 and the other major HIV-1 coreceptor CCR5 even in the absence of gp120 as demonstrated by CD4 coimmunoprecipitation with anti-CCR5 antibodies. Further, the amount of gp120-CD4-CXCR4 (or CCR5) complexes was proportional to the extent of cell fusion mediated by the HIV-1 Env (LAV or JRFL, respectively). These results demonstrate that of all the major types of host cells important for HIV-1 infection, the first central stage in the entry mechanism, the formation of gp120-CD4-coreceptor complexes, is not impaired except for the formation of the gp120-CD4-CXCR4 complex in macrophages. Therefore, for most CD4+ target cells restraint(s) on productive HIV-1 infection appears to occur at stages of the virus life cycle subsequent to the gp120-CD4-coreceptor complex formation.

Xiao X ，Kinter A ，Broder CC ，Dimitrov DS ... -  《EXPERIMENTAL AND MOLECULAR PATHOLOGY》