The Genetics of HIV Coreceptors and Coreceptor Ligands

CCR5 is the main coreceptor used by macrophage (M)-tropic strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), and is therefore essential for transmission of the disease. CXCR4 is the coreceptor for (T)-tropic strains. CCR5 binds a number of CC-chemokines, including MIP-1a, MIP-1b, RANTES, MCP-2 and MCP-3, while CXCR4 has only a single ligand, SDF-1. A number of genetic variants of genes encoding coreceptors and their ligands have been described, and some of these variants have been associated with resistance to HIV infection and/or disease progression. We review here the data accumulated so far concerning the variants of the CCR5, CCR2, SDF-1 and RANTES genes. For some of these variants, there is strong experimental evidence linking the modification of gene function with the phenotype of HIV resistance. In other cases, no functional alteration of the encoded proteins has been found, and the link between genotype and associated phenotype has not been demonstrated so far. The best characterized mutant is the ∆32 deletion mutant of the CCR5 gene, resulting in a non-functional protein that is not transported to the cell surface. Homozygotes for the ∆32 allele exhibit a strong, although incomplete, resistance to HIV infection. Heterozygotes were shown to display retarded progression to AIDS in most studies. Many other mutations of CCR5 have been described, some of which lead to non-functional receptors. These variants are, however, relatively rare and are incompletely characterized so far. Sequence variants in the CCR5 gene promoter have been reported, but the link with CCR5 expression is not clearly established, and the influence of these variant alleles on HIV infection and AIDS progression will require confirmation. A variant allele of CCR2 (CCR2-64I) was associated to delayed AIDS progression. This association was confirmed in several (but not all) studies, but the link between a fully functional variant of a minor coreceptor and the observed phenotype is presently unclear. A variant of the SDF-1 gene affecting a single nucleotide in the 3’ non-coding region of the transcript was associated with delayed progression in homozygotes. This association was, however, not found in several other studies, and no modification of gene function could be demonstrated so far. A recently reported variant of the RANTES gene promoter, providing retarded progression, will also require confirmation in independent studies. As a rule, care must be taken before taking an apparent association between a genotype and a phenotype for granted, until functional data supporting a causality link between the variables is clearly established.