Constitutive cell surface association between CD4 and CCR5.
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.
Xiao
X
X
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.
Wu
L
L
Stantchev
T S
TS
Feng
Y R
YR
Ugolini
S
S
Chen
H
H
Shen
Z
Z
Riley
J L
JL
Broder
C C
CC
Sattentau
Q J
QJ
Dimitrov
D S
DS
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
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5