Multiple nonfunctional alleles of CCR5 are frequent in various human populations

Abstract

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 (CCR5Δ32) 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-1β with affinities similar to wtCCR5, respond functionally to chemokines, and act as HIV-1 coreceptors. In addition to Δ32, 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-1α, MIP-1β, and RANTES. In addition to Δ32, 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.

CCR5 susceptibility to ligand-mediated down-modulation differs between human T lymphocytes and myeloid cells

“…1A ); some of which were previously used to study CCR5 conformations [ 35 , 37 ]. Five of these mAbs (MC5, CTC5, 45502, T21/8, and CTC8) have been mapped to the N-terminal domain of CCR5 [ 47 , 48 ]. MC5, 45502, and CTC5 recognize the first amino acid residues of CCR5 with expected overlapping binding sites, but only MC5 appears to recognize a linear epitope [ 37 , 47 , 49 ].…”

Host factors influencing susceptibility to HIV infection and AIDS progression

“…Other mutations (e.g. C20S and C269F) affect the formation of disulfide bridges, altering surface expression of the receptor and the ability to bind ligands [ 49 ]. Some mutations result in undetectable or very low levels of surface receptor (C269F, G106R, C101X).…”

“…Unlike Δ32, most of these CCR5 variants are relatively rare (frequencies below 1–2%) and only present in specific populations. Thus, their role in HIV-1 disease progression has not been properly established [ 17 , 49 , 50 ]. Interestingly, the rare C20S, C101X (also called m303), and T303A alleles are over-represented in EU individuals also carrying the more common CCR5Δ32 allele [ 51 , 52 ].…”

Association of Diverse Genotypes and Phenotypes of Immune Cells and Immunoglobulins With the Course of HIV-1 Infection

“…The CCR5-59356C/T polymorphism had a mixed effect on disease progression in terms of CD4 + counts and VL ( 77 , 82 ), possibly due to the genetic profiles of the ethnicities involved. In vitro functional assays of several SNP of CCR5, including C20S, C178R, A29S, L55Q, C101X, and FS299 ( 83 ) resulted in aberrant expression on the cell surface, alteration of ligand binding affinity, or inability to mediate receptor activation, all of which could influence disease progression in vivo .…”