TY - JOUR
T1 - Effects of CCR5-δ32 and CCR2-64I alleles on HIV-1 disease progression
T2 - The protection varies with duration of infection
AU - Mulherin, Stephanie A.
AU - O'Brien, Thomas R.
AU - Ioannidis, John P.A.
AU - Goedert, James J.
AU - Buchbinder, Susan P.
AU - Coutinho, Roel A.
AU - Jamieson, Beth D.
AU - Meyer, Laurence
AU - Michael, Nelson L.
AU - Pantaleo, Giuseppe
AU - Rizzardi, G. Paolo
AU - Schuitemaker, Hanneke
AU - Sheppard, Haynes W.
AU - Theodorou, Ioannis D.
AU - Vlahov, David
AU - Rosenberg, Philip S.
PY - 2003/2/14
Y1 - 2003/2/14
N2 - 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.
AB - 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.
KW - AIDS
KW - Alleles
KW - CCR2
KW - CCR5
KW - Chemokine receptors
KW - HIV-1
UR - http://www.scopus.com/inward/record.url?scp=0037435775&partnerID=8YFLogxK
U2 - 10.1097/00002030-200302140-00012
DO - 10.1097/00002030-200302140-00012
M3 - Article
C2 - 12556692
AN - SCOPUS:0037435775
SN - 0269-9370
VL - 17
SP - 377
EP - 387
JO - AIDS
JF - AIDS
IS - 3
ER -