Causal pathways for CCR5 genotype and HIV progression

A homozygous 32-bp deletion in the gene encoding CCR5(1) a major coreceptor for HIV-1, leads to resistance to infection with HIV-1, and heterozygosity for the deletion is associated with delayed disease progression in persons infected with HIV-1. We investigated the effect of CCR5 heterozygosity on disease progression as measured by both CD4(+) T-cell count decline and the occurrence of clinical AIDS symptoms. Using a unified statistical model fo r CD4 count progression and AIDS development, we examined whether the effec t of CCR5 heterozygosity on clinical AIDS is direct or indirect through its effect on CD4 counts. Based on data from the Multicenter AIDS Cohort Study , we noted a protective effect of CCR5 heterozygosity on both CD4 cell coun t progression and on AIDS occurrence. Furthermore, we found that this prote ctive effect on the occurrence of AIDS was completely mediated through an e ffect on the CD4 marker. Additional adjustment for the effect of an initial viral load measurement indicate that CCR5 heterozygosity did not have pred ictive value for either CD4 progression or the development of AIDS beyond i ts association with early viral load.