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Effects of CCR5-Δ32 and CCR2-64I alleles on HIV-1 disease progression

2003; Lippincott Williams & Wilkins; Volume: 17; Issue: 3 Linguagem: Inglês

10.1097/00002030-200302140-00012

1473-5571

Stephanie A. Mulherin, Thomas R. OʼBrien, John P. A. Ioannidis, James J. Goedert, Susan Buchbinder, Roel A. Coutinho, Beth D. Jamieson, Laurence Meyer, Nelson L. Michael, Giuseppe Pantaleo, G. Paolo Rizzardi, Hanneke Schuitemaker, Haynes W. Sheppard, Ioannis Theodorou, David Vlahov, Philip S. Rosenberg,

Immune Cell Function and Interaction

Objective: To examine temporal variation in the effects of CCR5-Δ32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression. Design: Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia. Methods: We studied HIV-1 seroconverters of European (n = 1635) or African (n = 215) ancestry who had been genotyped for CCR5-Δ32 and CCR2-64I. We used Cox proportional hazards models with time-varying coefficients to determine whether the genetic protection against AIDS (1987 case definition) and death varied with time since seroconversion. Results: Protection against AIDS conferred by CCR5-Δ32 held constant at a 31% (RH 0.69, 95% CI 0.54, 0.88) reduction in risk over the course of HIV-1 infection, whereas protection against death held constant at a 39% reduction in risk (RH 0.61, 95% CI 0.45, 0.88). When the period from AIDS to death was isolated, the survival benefit of CCR5-Δ32 diminished 2 years after AIDS. Protection against AIDS conferred by CCR2-64I was greatest early in the disease course. Compared with individuals without CCR5-Δ32 or CCR2-64I, individuals with one or two copies of CCR2-64I had a 58% lower risk of AIDS during the first 4 years after seroconversion (RH 0.42, 95% CI 0.23, 0.76), a 19% lower risk during the subsequent 4 years (RH 0.81, 95% CI 0.59, 1.12), and no significant protection thereafter. Conclusion: The protection against AIDS provided by CCR5-Δ32 is continuous during the course of infection. In contrast, the protection provided by CCR2-64I is greatest early in the course of infection.