Effects of CCR5-Δ 32, CCR2-64I, and SDF-1 3′A Alleles on HIV-1 Disease Progression: An International Meta-Analysis of Individual-Patient Data

Effects of CCR5-Δ 32, CCR2-64I, and SDF-1 3′A Alleles on HIV-1 Disease Progression: An International Meta-Analysis of Individual-Patient Data

John P.A. Ioannidis, MD;
Philip S. Rosenberg, PhD;
James J. Goedert, MD;
Lesley J. Ashton, MPH, PhD;
Thomas L. Benfield, MD;
Susan P. Buchbinder, MD;
Roel A. Coutinho, MD, PhD;
Jesper Eugen-Olsen, MSc;
Teresa Gallart, MD;
Terese L. Katzenstein, MD, PhD;
Leondios G. Kostrikis, PhD;
Harmjan Kuipers, MSc;
Leslie G. Louie, MPH, PhD;
Simon A. Mallal, MBBS, FRACP;
Joseph B. Margolick, MD, PhD;
Olga P. Martinez, MBBS, FRACP;
Laurence Meyer, MD, PhD;
Nelson L. Michael, MD, PhD;
Eva Operskalski, PhD, MBA;
Giusseppe Pantaleo, MD;
G. Paolo Rizzardi, MD;
Hanneke Schuitemaker, PhD;
Haynes W. Sheppard, PhD;
Graeme J. Stewart, MD, PhD;
Ioannis D. Theodorou, MD, PhD;
Henrik Ullum, MD, PhD;
Elisa Vicenzi, PhD;
David Vlahov, PhD;
David Wilkinson, PhD;
Cassy Workman, MBBS;
Jean-Francois Zagury, MD, PhD;
Thomas R. O'Brien, MD, MPH; and
for the International Meta-Analysis of HIV Host Genetics

From University of Ioannina School of Medicine, Ioannina, Greece; National Cancer Institute, National Institutes of Health, Bethesda, Maryland; National Center in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Hvidovre Hospital, Copenhagen, Denmark; San Francisco Department of Public Health, San Francisco, California; Municipal Health Service Amsterdam, Department of Public Health and Environment, Amsterdam, the Netherlands; Hospital Clinic Universitari, Barcelona, Spain; Rigshospitalet, Copenhagen, Denmark; Aaron Diamond AIDS Research Center, New York, New York; HIV R&D Group, Australian Red Cross Blood Service, Sydney, Australia; Children's Hospital Oakland Research Institute, Oakland, California; Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth, Australia; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Hopital de Bicetre, Le Kremlin–Bicetre, France; Walter Reed Army Institute of Research, Rockville, Maryland; University of Southern California, Los Angeles, California; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Central Laboratory of the Netherlands Red Cross Transfusion Service, Amsterdam, the Netherlands; California Department of Health Services, Berkeley, California; Westmead Hospital, Westmead, Australia; Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris, France; San Raffaele Scientific Institute, Milan, Italy; University of Texas Southwestern Medical Center, Dallas, Texas; AIDS Research Initiative, Darlinghurst, Australia; and Université Pierre et Marie Curie, Paris, France.

Abstract

Background: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results.

Objective: To examine postulated associations of genetic alleles with HIV-1 disease progression.

Design: Meta-analysis of individual-patient data.

Setting: 19 prospective cohort studies and case–control studies from the United States, Europe, and Australia.

Patients: Patients with HIV-1 infection who were of European or African descent.

Measurements: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models.

Results: Both the CCR5-Δ 32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, −0.18 log₁₀ copies/mL and −0.14 log₁₀ copies/mL; P < 0.05 for both). Having the CCR5-Δ32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3′A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all).

Conclusions: The CCR5-Δ 32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3′A homozygosity carried no such protection.

Article and Author Information

Acknowledgments: The authors thank Franklin J. Demuth for assistance with data management and Jennifer L. Martin and Julie Russell Grey for logistical support.
Requests for Single Reprints: Thomas R. O'Brien, MD, MPH, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 8016, Rockville, MD 20852; e-mail, obrient{at}exchange.nih.gov.
Current Author Addresses: Dr. Ioannidis: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.
Drs. Rosenberg, Goedert, and O'Brien: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Bethesda, MD 20852.
Dr. Ashton: National Center in HIV Epidemiology and Clinical Research, 376 Victoria Street, Sydney NSW 2010, Australia.
Dr. Benfield: Department of Infectious Diseases, Hvidovre Hospital, Kettegaard Alle, 30, Hvidovre, DK-2650, Denmark.
Dr. Buchbinder: HIV Research Section, San Francisco Department of Public Health, 25 Van Ness Avenue, #500, San Francisco, CA 94102-6033.
Dr. Coutinho: Municipal Health Service Amsterdam, Department of Public Health and Environment, Nieuwe Achtergracht 100, 1018 WT Amsterdam, the Netherlands.
Dr. Eugen-Olsen: Clinical Research Unit, Department 441, Hvidovre Hospital, DK-2650 Hvidovre, Denmark.
Dr. Gallart: Servei d'Immunologia, Hospital Clinic, Villaroel, 170, 08036 Barcelona, Spain.
Drs. Katzenstein and Ullum: Department of Infectious Diseases and Department of Clinical Immunology, Rigshospitalet, Blegdamsvej 9, Copenhagen E, DK-2100, Denmark.
Dr. Kostrikis: Department of Hygiene and Epidemiology, Athens University Medical School, Mikras Asias 75, Athens 11527, Greece.
Dr. Kuipers: Erasmus University, OR Molewater Plein 50, 3015 GE Rotterdam, the Netherlands.
Dr. Louie: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673.
Drs. Mallal and Martinez: Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Wellington Street, Perth, Western Australia 6000.
Dr. Margolick: Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205.
Dr. Meyer: Service d'Epidemiologie-INSERM U292, Hopital de Bicetre, 82 rue du general Leclerc, 94276 Le Kremlin-Bicetre Cedex, France.
Dr. Michael: Division of Retrovirology, Walter Reed Army Institute of Research, 1600 East Gude Drive, Rockville, MD 20850.
Dr. Operskalski: Department of Medicine, University of Southern California, 1640 Marengo Street, Los Angeles, CA 90033.
Drs. Pantaleo and Rizzardi: Centre Hospitalier Universitaire Vaudois, rue du Bugnon, 1005 Lausanne, Switzerland.
Dr. Schuitemaker: Department of Clinical Viro-Immunology, Central Laboratory of the Netherlands Red Cross Transfusion Service, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.
Dr. Sheppard: California Department of Health Services, 850 Marina Bay Parkway, Richmond, CA 94804.
Dr. Stewart: Department of Clinical Immunology, Westmead Hospital, Westmead NSW 2145, Australia.
Dr. Theodorou: INSERM u543, Bâtiment CERVI Hôpital de la Pitié Salpêtrière, 83 Boulevard de l'Hôpital, 75013 Paris, France.
Dr. Vicenzi: San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Dr. Vlahov: New York Academy of Medicine, 1216 5th Avenue, New York, NY 10029.
Dr. Wilkinson: Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8LS, Canada.
Dr. Workman: AIDS Research Initiative, Box 306, Sydney NSW 1300, Australia.
Dr. Zagury: Laboratoire de Physiologie Cellulaire, Université Pierre et Marie Curie, 4 Place Jussieu-Tour 32 −B.P. 198, 75252 Paris, Cedex 05, France.
Author Contributions: Conception and design: J.P.A. Ioannidis, P.S. Rosenberg, J.J. Goedert, L.J. Ashton, T.L. Benfield, R.A. Coutinho, T. Gallart, T.L. Katzenstein, L.G. Kostrikis, H. Kuipers, S.A. Mallal, N.L. Michael, E. Operskalski, G. Pantaleo, G.P. Rizzardi, H. Schuitemaker, H.W. Sheppard, G.J. Stewart, I.D. Theodorou, E. Vicenzi, D. Wilkinson, J.-F. Zagury, T.R. O'Brien.
Analysis and interpretation of the data: J.P.A. Ioannidis, P.S. Rosenberg, J.J. Goedert, J. Eugen-Olsen, J.B. Margolick, L. Meyer, N.L. Michael, T.R. O'Brien.
Drafting of the article: J.P.A. Ioannidis, P.S. Rosenberg, J.B. Margolick, N.L. Michael, I.D. Theodorou, T.R. O'Brien.
Critical revision of the article for important intellectual content: P.S. Rosenberg, J.J. Goedert, L.J. Ashton, T.L. Benfield, S.P. Buchbinder, R.A. Coutinho, J. Eugen-Olsen, T. Gallart, T.L. Katzenstein, L.G. Kostrikis, L.G. Louie, S.A. Mallal, J.B. Margolick, L. Meyer, N.L. Michael, E. Operskalski, G. Pantaleo, G.P. Rizzardi, H. Schuitemaker, H.W. Sheppard, G.J. Stewart, I.D. Theodorou, H. Ullum, E. Vicenzi, D. Vlahov, D. Wilkinson, J.-F. Zagury, T.R. O'Brien.
Final approval of the article: J.P.A. Ioannidis, P.S. Rosenberg, J.J. Goedert, L.J. Ashton, T.L. Benfield, S.P. Buchbinder, R.A. Coutinho, J. Eugen-Olsen, T. Gallart, T.L. Katzenstein, L.G. Kostrikis, H. Kuipers, L.G. Louie, S.A. Mallal, J.B. Margolick, O.P. Martinez, L. Meyer, N.L. Michael, E. Operskalski, G. Pantaleo, G.P. Rizzardi, H. Schuitemaker, H.W. Sheppard, G.J. Stewart, I.D. Theodorou, H. Ullum, E. Vicenzi, D. Vlahov, D. Wilkinson, C. Workman, J.-F. Zagury, T.R. O'Brien.
Provision of study materials or patients: J.J. Goedert, L.J. Ashton, T.L. Benfield, S.P. Buchbinder, R.A. Coutinho, J. Eugen-Olsen, T. Gallart, T.L. Katzenstein, L.G. Louie, S.A. Mallal, J.B. Margolick, O.P. Martinez, L. Meyer, N.L. Michael, E. Operskalski, G. Pantaleo, G.P. Rizzardi, I.D. Theodorou, H. Ullum, D. Vlahov, D. Wilkinson, C. Workman.
Statistical expertise: J.P.A. Ioannidis, P.S. Rosenberg, D. Vlahov.
Obtaining of funding: J.J. Goedert, L.G. Kostrikis, L. Meyer, H. Ullum, D. Vlahov, T.R. O'Brien.
Collection and assembly of data: J.P.A. Ioannidis, P.S. Rosenberg, J.J. Goedert, L.J. Ashton, T.L. Benfield, R.A. Coutinho, J. Eugen-Olsen, T. Gallart, T.L. Katzenstein, L.G. Louie, S.A. Mallal, J.B. Margolick, O.P. Martinez, L. Meyer, N.L. Michael, E. Operskalski, H. Schuitemaker, H. Ullum, D. Vlahov, C. Workman, T.R. O'Brien.