Distinctive effects of CCR5, CCR2, and SSDF1 genetic polymorphisms in AIDS progression

被引:86
作者
Hendel, H
Hénon, N
Lebuanec, H
Lachgar, A
Poncelet, H
Caillat-Zucman, S
Winkler, CA
Smith, MW
Kenefic, L
O'Brien, S
Lu, W
Andrieu, JM
Zagury, D
Schächter, F
Rappaport, J
Zagury, JF
机构
[1] Univ Paris 06, Physiol Cellulare Lab, F-75005 Paris, France
[2] Hop Pasteur, Nice, France
[3] Hosp Necker, Serv Immunol Clin, Paris, France
[4] NCI, FCRDC, Sci Applicat Int Co, Bethesda, MD 20892 USA
[5] NCI, Lab Genom Divers, Frederick, MD 21701 USA
[6] Hop Laennec, Serv Hematol Oncol, F-75340 Paris, France
[7] Allegheny Univ Hlth Sci, Ctr Neurovirol & Neurooncol, Philadelphia, PA 19102 USA
来源
JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY | 1998年 / 19卷 / 04期
关键词
CCR5; CCR2; SDF1; genetic polymorphisms; progression to AIDS;
D O I
10.1097/00042560-199812010-00009
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor (Fastprog) HIV-1-infected patients. Using this unique assembly, we performed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown to slow the rate of disease progression. The increased prevalence of mutant alleles among Slowprogs from the GRIV cohort was significant for CCR5 (p < .0001) but not for CCR2 (p = .09) or SDF1 (p = .12), emphasizing the predominant role of CCR5 as the major HIV-1 coreceptor. However, the prevalence of the CCR2 mutant allele (641) was significantly increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .04). The prevalence of double mutants SDF1-3'A/3'A genotypes was also increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations are overshadowed by the protective effects of the CCR5 deletion. Predictive biologic markers such as CD4 cell counts or viral load in the Slowprog population did not show significant differences between Slowprog groups with wild-type or mutant alleles for the three genes. Thus, our data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average duration of HIV infection is 12 years. We conclude that these genes, whose products serve as viral coreceptors or their ligands, may play a role early in infection and delay the onset of disease. However, among Slowprogs, whose duration of infection is >8 years, they are no longer influential for maintenance of their longterm nonprogression status. Other genetic determinants may be responsible for late protective effects.
引用
收藏
页码:381 / 386
页数:6
相关论文
共 22 条
[1]  
BALOTTA C, 1997, AIDS, V11, P67
[2]   HIV-1 infection in an individual homozygous for the CCR5 deletion allele [J].
Biti, R ;
French, RF ;
Young, J ;
Bennetts, B ;
Stewart, G ;
Liang, T .
NATURE MEDICINE, 1997, 3 (03) :252-253
[3]   Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors [J].
Cohen, OJ ;
Vaccarezza, N ;
Lam, GK ;
Baird, BF ;
Wildt, K ;
Murphy, PM ;
Zimmerman, PA ;
Nutman, TB ;
Fox, CH ;
Hoover, S ;
Adelsberger, J ;
Baseler, M ;
Arthos, J ;
Davey, RT ;
Dewar, RL ;
Metcalf, J ;
Schwartzentruber, DJ ;
Orenstein, JM ;
Buchbinder, S ;
Saah, AJ ;
Detels, R ;
Phair, J ;
Rinaldo, C ;
Margolick, JB ;
Pantaleo, G ;
Fauci, AS .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (06) :1581-1589
[4]   Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene [J].
Dean, M ;
Carrington, M ;
Winkler, C ;
Huttley, GA ;
Smith, MW ;
Allikmets, R ;
Goedert, JJ ;
Buchbinder, SP ;
Vittinghoff, E ;
Gomperts, E ;
Donfield, S ;
Vlahov, D ;
Kaslow, R ;
Saah, A ;
Rinaldo, C ;
Detels, R ;
OBrien, SJ .
SCIENCE, 1996, 273 (5283) :1856-1862
[5]  
DESOUZA MP, 1996, NAT MED, V2, P1293
[6]  
Guignard F, 1998, J IMMUNOL, V160, P985
[7]   Contribution of cohort studies in understanding HIV pathogenesis: Introduction of the GRIV cohort and preliminary results [J].
Hendel, H ;
Cho, YY ;
Gauthier, N ;
Rappaport, J ;
Schachter, F ;
Zagury, JF .
BIOMEDICINE & PHARMACOTHERAPY, 1996, 50 (10) :480-487
[8]   The role of a mutant CCR5 allele in HIV-1 transmission and disease progression [J].
Huang, YX ;
Paxton, WA ;
Wolinsky, SM ;
Neumann, AU ;
Zhang, LQ ;
He, T ;
Kang, S ;
Ceradini, D ;
Jin, ZQ ;
Yazdanbakhsh, K ;
Kunstman, K ;
Erickson, D ;
Dragon, E ;
Landau, NR ;
Phair, J ;
Ho, DD ;
Koup, RA .
NATURE MEDICINE, 1996, 2 (11) :1240-1243
[9]   Genetic effects on HIV disease progression [J].
Ioannidis, JPA ;
O'Brien, TR ;
Rosenberg, PS ;
Contopoulos-Ioannidis, DG ;
Goedert, JJ .
NATURE MEDICINE, 1998, 4 (05) :536-536
[10]   A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation [J].
Kostrikis, LG ;
Huang, YX ;
Moore, JP ;
Wolinsky, SM ;
Zhang, LQ ;
Guo, Y ;
Deutsch, L ;
Phair, J ;
Neumann, AU ;
Ho, DD .
NATURE MEDICINE, 1998, 4 (03) :350-353