Association between CCR5 Genotype and the Clinical Course of HIV-1 Infection

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Abstract
Heterozygosity for a 32-nucleotide deletion in the C-C chemokine receptor 5 gene (CCR5 delta32) is associated with delayed disease progression in persons infected with HIV-1. To compare the predictive value of CCR5 genotype with that of established markers in the clinical course of HIV-1 infection. Retrospective longitudinal study and nested case–control study. The latter included only long-term survivors, who were individually matched with progressors. Amsterdam, the Netherlands. 364 homosexual men with HIV-1 infection. Polymerase chain reaction was used for CCR5 genotyping. Univariate and multivariate Cox proportional-hazard analyses were done for disease progression with CCR5 genotype, CD4+ 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. In the case–control study, 48% of long-term survivors were heterozygous for CCR5 delta32 compared with 9% of progressors (odds ratio, 6.9 [95% CI, 1.9 to 24.8]). In the total study sample, CCR5 delta32 heterozygotes had significantly delayed disease progression (P < 0.001; relative hazard, 0.4 [CI, 0.3 to 0.6]), a 1.5-fold slower decrease in CD4+ T-lymphocyte count (P = 0.01), and a 2.6-fold lower viral RNA load (P = 0.01) at approximately 2.3 years after seroconversion 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 delta32 heterozygotes had a delayed conversion rate. The protective effect of CCR5 delta32 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 T-lymphocyte counts, T-lymphocyte function, and HIV-1 biological phenotype. The addition of CCR5 genotype to currently available laboratory markers may allow better estimation of the clinical course of HIV-1 infection.

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