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Association between CCR5 Genotype and the Clinical Course of HIV-1 Infection

Ana-Maria de Roda Husman, PhD; Maarten Koot, PhD; Marion Cornelissen, PhD; Ireneus P.M. Keet, MD, PhD; Margreet Brouwer, BSc; Silvia M. Broersen, BSc; Margreet Bakker, BSc; Marijke T.L. Roos, BSc; Maria Prins, MSc; Frank de Wolf, MD, PhD; Roel A. Coutinho, MD, PhD; Frank Miedema, PhD; Jaap Goudsmit, MD, PhD; and Hanneke Schuitemaker, PhD
[+] Article and Author Information

From the Central Laboratory of the Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam Academic Medical Center, and Municipal Health Service Amsterdam, Amsterdam, the Netherlands. Acknowledgments: The authors thank L. Berger, A. Holwerda, E. Hovenkamp, J. van de Hulst, and E. Poelstra for technical assistance and M.R. Klein and A.B. van 't Wout for critical reading of the manuscript. Grant Support: By the Netherlands Foundation for Preventive Medicine grant 28-2547 within the Stimulation Program AIDS Research of the Dutch Programme Committee for AIDS Research (Programma Coordinatie Commissie AIDS Onderzoele, grant 95-026). Requests for Reprints: Hanncke Schuitemaker, PhD, Department of Clinical Viro-Immunology, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands. Current Author Addresses: Drs. de Roda Husman, Koot, Miedema, and Schuitemaker. Ms. Brouwer, Ms. Broersen, and Ms. Roos: Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, Department of Clinical Viro-Immunology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1997;127(10):882-890. doi:10.7326/0003-4819-127-10-199711150-00004
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Background: Heterozygosity for a 32-nucleotide deletion in the C-C chemokine receptor 5 gene (CCR5 delta32) is associated with delayed disease progression in persons infected with HIV-1.

Objective: To compare the predictive value of CCR5 genotype with that of established markers in the clinical course of HIV-1 infection.

Design: Retrospective longitudinal study and nested case–control study. The latter included only long-term survivors, who were individually matched with progressors.

Setting: Amsterdam, the Netherlands.

Participants: 364 homosexual men with HIV-1 infection.

Measurements: Polymerase chain reaction was used for CCR5 genotyping. Univariate and multivariate Cox proportional-hazard analyses were done for disease progression with CCR5 genotype, CD4+ T-lymphocyte counts, T-lymphocyte function, HIV-1 biological phenotype (syncytium-inducing or non-syncytium-inducing HIV-1), and viral RNA load in serum as covariates.

Results: In the case–control study, 48% of long-term survivors were heterozygous for CCR5 delta32 compared with 9% of progressors (odds ratio, 6.9 [95% CI, 1.9 to 24.8]). In the total study sample, CCR5 delta32 heterozygotes had significantly delayed disease progression (P < 0.001; relative hazard, 0.4 [CI, 0.3 to 0.6]), a 1.5-fold slower decrease in CD4+ T-lymphocyte count (P = 0.01), and a 2.6-fold lower viral RNA load (P = 0.01) at approximately 2.3 years after seroconversion compared with CCR5 wild-type homozygotes. At the end of the study, both groups showed the same prevalence of syncytium-inducing HIV-1, but CCR5 delta32 heterozygotes had a delayed conversion rate. The protective effect of CCR5 delta32 heterozygosity was stronger in the presence of only non-syncytium-inducing HIV-1. The CCR5 genotype predicted disease progression independent of viral RNA load, CD4 T-lymphocyte counts, T-lymphocyte function, and HIV-1 biological phenotype.

Conclusions: The addition of CCR5 genotype to currently available laboratory markers may allow better estimation of the clinical course of HIV-1 infection.

Figures

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Figure 1.
C-C chemokine receptor 5 (CCR5) genotype and disease progression.leftright

Kaplan-Meier plots for time to development of AIDS ( ) or death ( ) for homozygotes (thin lines) and CCR5 delta32 heterozygotes (thick lines). The numbers of men at risk are indicated for each time point.

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Figure 2.
C-C chemokine receptor 5 (CCR5) genotype and mean CD4+ T-lymphocyte counts from the time of seroconversion.

White circles represent CD4+ T-lymphocyte counts for CCR5 wild-type homozygotes; black circles represent counts for CCR5 delta32 heterozygotes. Error bars represent SEs of the mean.

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Figure 3.
C-C chemokine receptor 5 (CCR5) genotype and serum viral load.

The probability distributions of serum viremia levels 1.5 to 3.0 years after seroconversion in CCR5 wild-type homozygotes (white bars) and CCR5 delta32 heterozygotes (striped bars) are shown.

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Figure 4.
C-C chemokine receptor 5 (CCR5) genotype and HIV-1 biological phenotype.topmiddlebottom

Kaplan-Meier plots for CCR5 delta32 heterozygotes (thick lines) and CCR5 wild-type homozygotes (thin lines) for time to emergence of syncytium-inducing HIV-1 ( ), time to AIDS for the period during which only non-sancytium-inducing variants were present ( ), and time to AIDS for the period after the emergence of syncytium-inducing HIV-1 ( ). Curves are cut off when fewer than 10 men are at risk.

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Figure 5.
Relation between C-C chemokine receptor 5 (CCR5) genotype and virologic and immunologic prognostic markers for progression to AIDS at 2 years (top) and 6 years after seroconversion (bottom).34

Kaplan-Meier plots show cumulative progression to AIDS. Participants were stratified according to the number of criteria that were fulfilled (CCR5 wild-type genotype, CD4+ T-lymphocyte count <500 cells/mm , and viral RNA level >10 .5 copies/mL at 2 years after seroconversion; CCR5 wild-type genotype, T-lymphocyte function less than 30% than the function of HIV-negative controls, and syncytium-inducing phenotype at 6 years after seroconversion). The dotted line indicates that none of the 3 criteria was met, the thick line indicates that 1 of the 3 criteria was met, the intermediate line indicates that 2 of the 3 criteria were met, and the thin line indicates that all 3 criteria were met. The numbers of men at risk are indicated for each time point. Curves are cut off when fewer than 10 men are at risk.

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