Multiple nonfunctional alleles of CCR5 are frequent in various human populations.
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 (CCR5Delta32) 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 [(125)I]-MIP-1beta with affinities similar to wtCCR5, respond functionally to chemokines, and act as HIV-1 coreceptors. In addition to Delta32, 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-1alpha, MIP-1beta, and RANTES. In addition to Delta32, 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. (Blood. 2000;96:1638-1645)
Blanpain
C
C
IRIBHN, Laboratoire d'Histologie, de Neuroanatomie et de Neuropathologie and Service de Génétique Médicale, Université Libre de Bruxelles, Bruxelles, Belgium.
Lee
B
B
Tackoen
M
M
Puffer
B
B
Boom
A
A
Libert
F
F
Sharron
M
M
Wittamer
V
V
Vassart
G
G
Doms
R W
RW
Parmentier
M
M
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D006224:Cricetinae; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D007457:Iodine Radioisotopes; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011869:Radioligand Assay; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D007457:Iodine Radioisotopes; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D008156:Luciferases