Disease relevance of CCR5

• As chimpanzees are the animal model for infection by HIV-1, we cloned and sequenced chimpanzee CXCR4 and CCR5 from PBMCs [1].
• Chimpanzee CXCR4 and CCR5 act as coreceptors for HIV type 1 [1].
• Evidence that variants in the 5' cis-regulatory region of CCR5 (5'CCR5) affect disease progression in humans suggests that variation in CCR5 might also influence the response of chimpanzees to HIV-1/SIVcpz [2].
• The R5-tropic primary SIVsm and HIV-2 strains grew in CCR5-negative human PBMC, consistent with their use of non-CCR5 coreceptors [3].

High impact information on CCR5

• SIVcpz and most strains of HIV-1 require the cell-surface receptor CC chemokine receptor 5 (CCR5) to infect specific leukocyte subsets, and, subsequent to infection, the level of CCR5 expression influences the amount of HIV-1 entry and the rate of HIV-1 replication [2].
• These results are strong evidence that balancing selection has shaped the pattern of variation in CCR5 and suggest that HIV-1 resistance afforded by CCR5 5' cis-regulatory region haplotypes may be the consequence of adaptive changes to older pathogens [4].
• We characterized CCR5 sequence variation in this region in 400 chromosomes from worldwide populations and compared it to a genome-wide analysis of 100 Alu polymorphisms typed in the same populations [4].
• Many of these polymorphisms are located in the 5' cis-regulatory region of CCR5, suggesting that it may have been a target of natural selection [4].
• In at least two animals, one infected AGM (Cercopithecus tantalus) and one noninfected monkey (Cercocebus aterrimus), the CCR5 alleles identified encode functional proteins, as they were identical in terms of amino acid sequence to that of functional CCR5 reported in the literature [5].

Biological context of CCR5

• A genealogy of CCR5 haplotypes had deep branch lengths despite markedly little differentiation among populations [4].
• This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes [6].
• Interestingly, the DNA sequence of the chimpanzee CCR-5 gene in the region including the site of the deltaccr-5 mutation, and flanking areas, was virtually identical to the homologous human sequence, only two mismatches (silent substitutions) were found [7].

Analytical, diagnostic and therapeutic context of CCR5

• CCR5 sequence analysis demonstrated that chimpanzee and baboon share 99.6 and 98% nucleotide homology and 100 and 98% amino acid homology, respectively, with the human sequence [8].

References