title: Constitutive cell surface association between CD4 and CCR5.
abstract: HIV-1 entry into cells involves formation of a complex between gp120 of the viral envelope glycoprotein (Env), a receptor (CD4), and a coreceptor. For most strains of HIV, this coreceptor is CCR5. Here, we provide evidence that CD4 is specifically associated with CCR5 in the absence of gp120 or any other receptor-specific ligand. The amount of CD4 coimmunoprecipitated with CCR5 was significantly higher than that with the other major HIV coreceptor, CXCR4, and in contrast to CXCR4 the CD4-CCR5 coimmunoprecipitation was not significantly increased by gp120. The CD4-CCR5 interaction probably takes place via the second extracellular loop of CCR5 and the first two domains of CD4. It can be inhibited by CCR5- and CD4-specific antibodies that interfere with HIV-1 infection, indicating a possible role in virus entry. These findings suggest a possible pathway of HIV-1 evolution and development of immunopathogenicity, a potential new target for antiretroviral drugs and a tool for development of vaccines based on Env-CD4-CCR5 complexes. The constitutive association of a seven-transmembrane-domain G protein-coupled receptor with another receptor also indicates new possibilities for cross-talk between cell surface receptors.
authors.affiliation: Laboratory of Experimental and Computational Biology, National Cancer Institute-Frederick Cancer Research and Development Center, National Institutes of Health, Miller Drive, Frederick, MD 21702-1201, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: T S
authors.initials: TS
authors.lastname: Stantchev
authors.forename: Y R
authors.initials: YR
authors.lastname: Feng
authors.forename: S
authors.initials: S
authors.lastname: Ugolini
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Shen
authors.forename: J L
authors.initials: JL
authors.lastname: Riley
authors.forename: C C
authors.initials: CC
authors.lastname: Broder
authors.forename: Q J
authors.initials: QJ
authors.lastname: Sattentau
authors.forename: D S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D016475:3T3 Cells; D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology*; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D019713:Receptors, CCR5 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5