CONTRASTING GENETIC INFLUENCE OF CCR2 AND CCR5 VARIANTS ON HIV-1 INFECTION AND DISEASE PROGRESSION

The critical role of chemokine receptors (CCR5 and CXCR4) in human imm unodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that med iate HIV-1 disease progression, A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent am ong Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I a llele progressed to AIDS 2 to 4 years later than individuals homozygou s for the common allele. Because CCR2-64I occurs invariably on a CCR5- +-bearing chromosomal haplotype, the independent effects of CCR5-Delta 32 (which also delays AIDS onset) and CCR2-64I were determined. An es timated 38 to 45 percent of AIDS patients whose disease progresses rap idly (less than 3 years until onset of AIDS symptoms after HIV-1 expos ure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AI DS for 16 years or more, can be explained by a mutant genotype for CCR 2 or CCR5.