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Inherited Resistance to HIV-1 Conferred by an Inactivating Mutation in CC Chemokine Receptor 5: Studies in Populations with Contrasting Clinical Phenotypes, Defined Racial Background, and Quantified Risk

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Abstract

Background

CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus-1 (HIV-1). Recently, an inactive CCR5 allele (designated here as CCR5-2) was identified that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. The reports conflict on the effect of heterozygous CCR5-2 on HIV-1 susceptibility, and race and risk levels have not yet been fully analyzed. Here we report our independent identification of CCR5-2 and test its effects on HIV-1 pathogenesis in individuals with contrasting clinical outcomes, defined race, and quantified risk.

Materials and Methods

Mutant CCR5 alleles were sought by directed heteroduplex analysis of genomic DNA from random blood donors. Genotypic frequencies were then determined in (1) random blood donors from North America, Asia, and Africa; (2) HIV-1 + individuals; and (3) highly exposed-seronegative homosexuals with quantified risk.

Results

CCR5-2 was the only mutant allele found. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in highly exposed-seronegative (4.5%, n = 111) and HIV-1-seropositive (0%, n = 614) Caucasians relative to Caucasian random blood donors (0.8%, n = 387). This difference was highly significant (p < 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same three groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of two cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1+ Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Moreover, Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconvertors had a 52.6% lower risk of developing AIDS than homozygous wild-type seroconvertors.

Conclusions

The data suggest that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. Since the majority (∼96%) of highly exposed-seronegative individuals tested are not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of novel antiretroviral therapy.

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Acknowledgments

We dedicate this study to Michael Chopek, M.D., our friend and colleage, who died suddenly on October 31, 1996. We thank M. Connor for patient samples; H.C. Lane, L. Schrager, J. Metcalf, S. Vogel, M. Polis, S. McCoy, C. Kleeberger, J. Phair, S. Wu, L. Jacobson, A. Munoz, and M. Majchrowicz for help in obtaining samples and for retrieval of coded clinical information; R. Plishka for DNA sequencing; M. Martin, J. Phair, J. Gallin, and H. Malech for helpful advice; D. Alling, C. Kleeberger, L. Jacobson, and A. Munoz for statistical advice; and the patients and clinical research staff of the MACS centers and the AIDS Clinic, NIAID, for making the DNA samples and clinical data analyzed in this study available. Samples and data provided by the Multicenter AIDS Cohort Study (MACS) were contributed by centers (principal investigators) at Johns Hopkins School of Public Health (A. Saah, A. Munoz, J. Margolick); Harold Brown Health Center and Northwestern University Medical School (J. Phair); University of California, Los Angeles (R. Detels, J.V. Giorgi); and University of Pittsburgh (C. Rinaldo). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the Agency for Health Care Policy and Research: UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-37613, UO1-AI-35041.

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Authors and Affiliations

  1. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4, Rm 126, Bethesda, Maryland, 2089-0425, USA

    Peter A. Zimmerman, Joseph Kubofcik &  Thomas B. Nutman

  2. Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Ghalib Alkhatib, Paul E. Kennedy & Edward A. Berger

  3. Laboratory of Host Defenses, National Institutes of Health, Bldg. 10, Rm 11N-113, Bethesda, Maryland, 20892, USA

    Christophe Combadiere &  Philip M. Murphy

  4. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Drew Weissman, Oren Cohen, Andrea Rubbert, Gordon Lam, Mauro Vaccarezza & Anthony S. Fauci

  5. Division of Molecular Virology and Immunology, Georgetown University, Rockville, Maryland, USA

    Alicia Buckler-White

  6. National HLA Histocompatibility Laboratory, American Red Cross, University of Maryland Medical System, Baltimore, Maryland, USA

    Todd Spalding, Jay Hunter & Michael Chopek

  7. Tuberculosis Research Centre, Spur Tank Road, Chetput, Madras, India

    V. Kumaraswami

  8. Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA

    Janis V. Giorgi

  9. Department of Epidemiology, UCLA School of Public Health, Los Angeles, California, USA

    Roger Detels

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  1. Peter A. Zimmerman
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  2. Alicia Buckler-White
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  7. Drew Weissman
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  8. Oren Cohen
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  9. Andrea Rubbert
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  10. Gordon Lam
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  11. Mauro Vaccarezza
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  12. Paul E. Kennedy
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  13. V. Kumaraswami
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  14. Janis V. Giorgi
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  15. Roger Detels
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  16. Jay Hunter
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  17. Michael Chopek
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  18. Edward A. Berger
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  19. Anthony S. Fauci
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  20. Thomas B. Nutman
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  21. Philip M. Murphy
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Additional information

The nucleic acid sequence of CCR5-2 has been deposited in Genbank, #U66285.

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Zimmerman, P.A., Buckler-White, A., Alkhatib, G. et al. Inherited Resistance to HIV-1 Conferred by an Inactivating Mutation in CC Chemokine Receptor 5: Studies in Populations with Contrasting Clinical Phenotypes, Defined Racial Background, and Quantified Risk. Mol Med 3, 23–36 (1997). https://doi.org/10.1007/BF03401665

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