Association between CCR5 genotype and the clinical course of HIV-1 infection

Background: Heterozygosity for a 32-nucleotide deletion in the C-C chemokine receptor 5 gene (CCR5 A32) is associated with delayed disease progression in persons infected with HIV-1. Objective: To compare the predictive value of CCR5 genotype with that of established markers in the clinical course of HIV-1 infection. Design: Retrospective longitudinal study and nested case-control study. The latter included only long-term survivors, who were individually matched with progressors. Setting: Amsterdam, the Netherlands. Participants: 364 homosexual men with HIV-1 infection. Measurements: Polymerase chain reaction was used for CCR5 genotyping. Univariate and multivariate Cox proportional hazard analyses were done for disease progression with CCR5 genotype, [CD4.sup.+] T-lymphocyte counts, T-lymphocyte function, HIV-1 biological phenotype (syncytium-inducing or non-syncytium-inducing HIV-1), and viral RNA load in serum as covariates. Results: In the case-control study, 48% of long-term survivors were heterozygous for CCR5 A32 compared with 9% of progressors (odds ratio, 6.9 [95% Cl, 1.9 to 24.8]). In the total study sample, CCR5 A32 heterozygotes had significantly delayed disease progression (P < 0.001; relative hazard, 0.4 [Cl, 0.3 to 0.6]), a 1.5-fold slower decrease in [CD4.sup.+] T-lymphocyte count (P = 0.01), and a 2.6-fold lower viral RNA load (P = 0.01) at approximately 2.3 years after sero-conversion compared with CCR5 wild-type homozygotes. At the end of the study, both groups showed the same prevalence of syncytium-inducing HIV-1, but CCR5 A32 heterozygotes had a delayed conversion rate. The protective effect of CCR5 [Delta]32 heterozygosity was stronger in the presence of only non-syncytium-inducing HIV-1. The CCR5 genotype predicted disease progression independent of viral RNA load, [CD4.sub.+] T-lymphocyte counts, T-lymphocyte function, and HIV-1 biological phenotype. Conclusions: The addition of CCR5 genotype to currently available laboratory markers may allow better estimation of the clinical course of HIV-1 infection.
A genetic variation called heterozygosity for a 32-nucleotide deletion in the C-C chemokine receptor 5 gene (CCR5 delta 32) may slow disease progression in patients infected with the HIV-1 virus. The genes of 364 homosexual men with HIV were analyzed and they were followed using independent markers of disease progression. Those with the heterozygote variation showed significant delays in disease progression with slower decreases in T-lymphocytes and lower viral loads compared to men without the variation. A total of 48% of the long term survivors had this genetic variation, compared to 9% of those with progressive disease.