DISTINCTIVE EFFECTS OF CCR5, CCR2, AND SSDF1 GENETIC POLYMORPHISMS INAIDS PROGRESSION

The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represe nts 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progresso r (Fastprog) HIV-1-infected patients. Using this unique assembly, we p erformed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown to slow the rate of disea se progression. The increased prevalence of mutant alleles among Slowp rogs from the GRIV cohort was significant for CCR5 (p < .0001) but not for CCR2 (p = .09) or SDF1 (p = .12), emphasizing the predominant rol e of CCR5 as the major HIV-1 coreceptor. However, the prevalence of th e CCR2 mutant allele (641) was significantly increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .04). The prevalence of double mutants SDF1-3'A/3'A genotypes was also increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations are overshadowe d by the protective effects of the CCR5 deletion. Predictive biologic markers such as CD4 cell counts or viral load in the Slowprog populati on did not show significant differences between Slowprog groups with w ild-type or mutant alleles for the three genes. Thus, our data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average dur ation of HIV infection is 12 years. We conclude that these genes, whos e products serve as viral coreceptors or their ligands, may play a rol e early in infection and delay the onset of disease. However, among Sl owprogs, whose duration of infection is >8 years, they are no longer i nfluential for maintenance of their longterm nonprogression status. Ot her genetic determinants may be responsible for late protective effect s.