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 th
at 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 corecepto
r, CXCR4, and in contrast to CXCR4 the CD4-CCR5 coimmunoprecipitation Was n
ot significantly increased by gp120. The CD4-CCR5 interaction probably take
s 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 inter
fere 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 EnvCD4-CCR5 complexes. The consti
tutive association of a seven-transmembrane-domain G protein-coupled recept
or with another receptor also indicates new possibilities for cross talk be
tween cell surface receptors.