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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1638-1645
PLENARY PAPER
Multiple nonfunctional alleles of CCR5 are frequent in various
human populations
Cédric Blanpain,
Benhur Lee,
Marie Tackoen,
Bridget Puffer,
Alain Boom,
Frédérick Libert,
Mathew Sharron,
Valérie Wittamer,
Gilbert Vassart,
Robert W. Doms, and
Marc Parmentier
From the IRIBHN, Laboratoire d'Histologie, de
Neuroanatomie et de Neuropathologie and Service de
Génétique Médicale, Université Libre de
Bruxelles, Bruxelles, Belgium; and Department of Pathology and
Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
CCR5 is the major coreceptor for macrophage-tropic strains of
the human immunodeficiency virus type I (HIV-1). Homozygotes for a
32-base pair (bp) deletion in the coding sequence of the receptor
(CCR5 32) were found to be highly resistant to viral infection, and
CCR5 became, therefore, one of the paradigms illustrating the influence
of genetic variability onto individual susceptibility to infectious and
other diseases. We investigated the functional consequences of 16 other
natural CCR5 mutations described in various human populations. We found
that 10 of these variants are efficiently expressed at the cell
surface, bind [125I]-MIP-1 with affinities similar to
wtCCR5, respond functionally to chemokines, and act as HIV-1
coreceptors. In addition to 32, six mutations were characterized by
major alterations in their functional response to chemokines, as a
consequence of intracellular trapping and poor expression at the cell
surface (C101X, FS299), general or specific alteration of ligand
binding affinities (C20S, C178R, A29S), or relative inability to
mediate receptor activation (L55Q). A29S displayed an unusual
pharmacological profile, binding and responding to MCP-2 similarly to
wtCCR5, but exhibiting severely impaired binding and functional
responses to MIP-1 , MIP-1, and RANTES. In addition to 32,
only C101X was totally unable to mediate entry of HIV-1. The fact that
nonfunctional CCR5 alleles are relatively frequent in various human
populations reinforces the hypothesis of a selective pressure favoring
these alleles.
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