Multiple nonfunctional alleles of CCR5 are frequent in various human populations

CCR5 is the major coreceptor for macrophage-tropic strains of the human imm unodeficiency virus type I(HIV-1), Homozygotes for a 32-base pair (bp) dele tion in the coding sequence of the receptor (CCR5 Delta 32) were found to b e highly resistant to viral infection, and CCR5 became, therefore, one of t he paradigms illustrating the influence of genetic variability onto individ ual susceptibility to infectious and other diseases. We investigated the fu nctional consequences of 16 other natural CCR5 mutations described in vario us human populations. We found that 10 of these variants are efficiently ex pressed at the cell surface, bind [I-125]-MIP-1 beta with affinities simila r to wtCCR5, respond functionally to chemokines, and act as HIV-1 corecepto rs. In addition to Delta 32, six mutations were characterized by major alte rations in their functional response to chemokines, as a consequence of int racellular 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 di splayed an unusual pharmacological profile, binding and responding to MCP-2 similarly to wtCCR5, but exhibiting severely impaired binding and function al responses to MIP-1 alpha, MIP-1 beta, and RANTES, In addition to Delta 3 2, only C101X was totally unable to mediate entry of HIV-1. The fact that n onfunctional CCR5 alleles are relatively frequent in various human populati ons reinforces the hypothesis of a selective pressure favoring these allele s, (C) 2000 by The American Society of Hematology.