EARLY PROTECTIVE EFFECT OF CCR-5 DELTA-32 HETEROZYGOSITY ON HIV-1 DISEASE PROGRESSION - RELATIONSHIP WITH VIRAL LOAD

Objective: To determine the influence of heterozygosity for the Delta 32 mutant CCR-5 allele on HIV-1 disease progression. Design: HIV-1 dis ease progression and serum viral load were analysed according to the C -C chemokine receptor (CCR)-5 genotype in 412 Caucasian patients (319 men and 93 women) with a known date of seroconversion, who were enroll ed in the SEROCO cohort (median follow-up, 74 months). Results: The fr equency of heterozygosity for the mutant allele was 17% and did not di ffer according to sex or risk factor for HIV infection. Heterozygotes were significantly less likely than patients with two functional allel es to have symptomatic primary infection. Their serum viral load was l ower during the 6- to 24-month plateau phase after seroconversion. Thi s difference persisted afterwards, although the rate of decline in CD4 + cells was similar. Kaplan-Meier survival curves showed slower progre ssion to clinical AIDS in heterozygotes during the first 7 years follo wing infection (P< 0.02), the two curves tending to join thereafter (o verall log-rank lest, P = 0.17). However, the interaction term with ti me did not reach significance in a Cox model. The overall relative ris k of progression was 0.67 (95% confidence interval, 0.38-1.18) and was not influenced by adjustment for age at seroconversion or symptomatic primary infection. After adjustment for early viral load the relative risk was 0.83. Pneumocystis carinii pneumonia and toxoplasmosis were less likely to be the first AIDS-defining illness in heterozygotes tha n in the other patients (0 versus 24.7% of AIDS cases, P= 0.04), despi te similar management. Conclusion: Deletion of one CCR-5 gene allele a ppears to protect against HIV-1 disease progression, mainly during the early years of the infection. Heterozygosity for the deletion leads t o persistently lower viral load, and also seems to protect against som e opportunistic infections.