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Relation of HLA class I and II supertypes with spontaneous clearance of hepatitis C virus

Genes & Immunity volume 14, pages 330–335 (2013)Cite this article

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Abstract

Human leukocyte antigen (HLA) genotype has been associated with the probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; P=0.004) was associated with HCV persistence, whereas DR8 (PR=1.8; P=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became nonsignificant in analysis that included supertypes, whereas B*57:03 (PR=1.9; P=0.008) and DRB1*07:01 (PR=1.7; P=0.005) retained their significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance.

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References

  1. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ . The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144: 705–714.

    Article  Google Scholar 

  2. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP . The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45: 529–538.

    Article  Google Scholar 

  3. Thimme R, Neumann-Haefelin C, Boettler T, Blum HE . Adaptive immune responses to hepatitis C virus: from viral immunobiology to a vaccine. Biol Chem 2008; 389: 457–467.

    Article  CAS  Google Scholar 

  4. Burke KP, Cox AL . Hepatitis C virus evasion of adaptive immune responses: a model for viral persistence. Immunol Res 2010; 47: 216–227.

    Article  CAS  Google Scholar 

  5. Chang KM, Rehermann B, McHutchison JG, Pasquinelli C, Southwood S, Sette A et al. Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus. J Clin Invest 1997; 100: 2376–2385.

    Article  CAS  Google Scholar 

  6. Kuniholm MH, Kovacs A, Gao X, Xue X, Marti D, Thio CL et al. Specific human leukocyte antigen class I and II alleles associated with hepatitis C virus viremia. Hepatology 2010; 51: 1514–1522.

    Article  CAS  Google Scholar 

  7. Sidney J, del Guercio MF, Southwood S, Engelhard VH, Appella E, Rammensee HG et al. Several HLA alleles share overlapping peptide specificities. J Immunol 1995; 154: 247–259.

    CAS  PubMed  Google Scholar 

  8. Sidney J, Grey HM, Kubo RT, Sette A . Practical, biochemical and evolutionary implications of the discovery of HLA class I supermotifs. Immunol Today 1996; 17: 261–266.

    Article  CAS  Google Scholar 

  9. Lazaryan A, Lobashevsky E, Mulenga J, Karita E, Allen S, Tang J et al. Human leukocyte antigen B58 supertype and human immunodeficiency virus type 1 infection in native Africans. J Virol 2006; 80: 6056–6060.

    Article  CAS  Google Scholar 

  10. Lazaryan A, Song W, Lobashevsky E, Tang J, Shrestha S, Zhang K et al. Human leukocyte antigen class I supertypes and HIV-1 control in African Americans. J Virol 2010; 84: 2610–2617.

    Article  CAS  Google Scholar 

  11. Trachtenberg E, Korber B, Sollars C, Kepler TB, Hraber PT, Hayes E et al. Advantage of rare HLA supertype in HIV disease progression. Nat Med 2003; 9: 928–935.

    Article  CAS  Google Scholar 

  12. Chang KM, Gruener NH, Southwood S, Sidney J, Pape GR, Chisari FV et al. Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis C. J Immunol 1999; 162: 1156–1164.

    CAS  PubMed  Google Scholar 

  13. Wentworth PA, Sette A, Celis E, Sidney J, Southwood S, Crimi C et al. Identification of A2-restricted hepatitis C virus-specific cytotoxic T lymphocyte epitopes from conserved regions of the viral genome. Int Immunol 1996; 8: 651–659.

    Article  CAS  Google Scholar 

  14. Greenbaum J, Sidney J, Chung J, Brander C, Peters B, Sette A . Functional classification of class II human leukocyte antigen (HLA) molecules reveals seven different supertypes and a surprising degree of repertoire sharing across supertypes. Immunogenetics 2011; 63: 325–335.

    Article  CAS  Google Scholar 

  15. Lund O, Nielsen M, Kesmir C, Petersen AG, Lundegaard C, Worning P et al. Definition of supertypes for HLA molecules using clustering of specificity matrices. Immunogenetics 2004; 55: 797–810.

    Article  CAS  Google Scholar 

  16. Nielsen M, Lundegaard C, Blicher T, Peters B, Sette A, Justesen S et al. Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan. PLoS Comput Biol 2008; 4: e1000107.

    Article  Google Scholar 

  17. Ou D, Mitchell LA, Tingle AJ . A new categorization of HLA DR alleles on a functional basis. Hum Immunol 1998; 59: 665–676.

    Article  CAS  Google Scholar 

  18. Harris RA, Sugimoto K, Kaplan DE, Ikeda F, Kamoun M, Chang KM . Human leukocyte antigen class II associations with hepatitis C virus clearance and virus-specific CD4 T cell response among Caucasians and African Americans. Hepatology 2008; 48: 70–79.

    Article  Google Scholar 

  19. Sette A, Sidney J . Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 1999; 50: 201–212.

    Article  CAS  Google Scholar 

  20. Yu XG, Lichterfeld M, Chetty S, Williams KL, Mui SK, Miura T et al. Mutually exclusive T-cell receptor induction and differential susceptibility to human immunodeficiency virus type 1 mutational escape associated with a two-amino-acid difference between HLA class I subtypes. J Virol 2007; 81: 1619–1631.

    Article  CAS  Google Scholar 

  21. Eyster ME, Sanders J, Goedert JJ . Viral clearance occurs very early during the natural resolution of hepatitis C virus infection in persons with haemophilia. Haemophilia 2004; 10: 75–80.

    Article  CAS  Google Scholar 

  22. Raghuraman S, Park H, Osburn WO, Winkelstein E, Edlin BR, Rehermann B . Spontaneous clearance of chronic hepatitis C virus infection is associated with appearance of neutralizing antibodies and reversal of T-cell exhaustion. J Infect Dis 2012; 205: 763–771.

    Article  CAS  Google Scholar 

  23. Cano P, Fan B, Stass S . A geometric study of the amino acid sequence of class I HLA molecules. Immunogenetics 1998; 48: 324–334.

    Article  CAS  Google Scholar 

  24. Tong JC, Tan TW, Ranganathan S . In silico grouping of peptide/HLA class I complexes using structural interaction characteristics. Bioinformatics 2007; 23: 177–183.

    Article  CAS  Google Scholar 

  25. Mohanapriya A, Nandagond S, Shapshak P, Kangueane U, Kangueane P . A HLA-DRB supertype chart with potential overlapping peptide binding function. Bioinformation 2010; 4: 300–309.

    Article  Google Scholar 

  26. Kangueane P, Sakharkar MK, Rajaseger G, Bolisetty S, Sivasekari B, Zhao B et al. A framework to sub-type HLA supertypes. Front Biosci 2005; 10: 879–886.

    Article  CAS  Google Scholar 

  27. Doytchinova IA, Guan P, Flower DR . Identifiying human MHC supertypes using bioinformatic methods. J Immunol 2004; 172: 4314–4323.

    Article  CAS  Google Scholar 

  28. Hertz T, Yanover C . Identifying HLA supertypes by learning distance functions. Bioinformatics 2007; 23: e148–e155.

    Article  CAS  Google Scholar 

  29. Reche PA, Reinherz EL . Definition of MHC supertypes through clustering of MHC peptide-binding repertoires. Methods Mol Biol 2007; 409: 163–173.

    Article  CAS  Google Scholar 

  30. Sidney J, Peters B, Frahm N, Brander C, Sette A . HLA class I supertypes: a revised and updated classification. BMC Immunol 2008; 9: 1.

    Article  Google Scholar 

  31. Doytchinova IA, Flower DR . In silico identification of supertypes for class II MHCs. J Immunol 2005; 174: 7085–7095.

    Article  CAS  Google Scholar 

  32. Kuo CL, Feingold E . What’s the best statistic for a simple test of genetic association in a case-control study? Genet Epidemiol 2010; 34: 246–253.

    Article  Google Scholar 

  33. Pybus OG, Cochrane A, Holmes EC, Simmonds P . The hepatitis C virus epidemic among injecting drug users. Infect Genet Evol 2005; 5: 131–139.

    Article  Google Scholar 

  34. Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    Article  CAS  Google Scholar 

  35. Westfall PH, Young SS . Resampling-Based Multiple Testing: Examples and Methods for P-Value Adjustment. Wiley-Interscience: New York, NY, 1993.

    Google Scholar 

  36. Nielsen M, Justesen S, Lund O, Lundegaard C, Buus S . NetMHCIIpan-2.0—Improved pan-specific HLA-DR predictions using a novel concurrent alignment and weight optimization training procedure. Immunome Res 2010; 6: 9.

    Article  Google Scholar 

Download references

Acknowledgements

Funding for the current project was provided in part by R01AI057006 (HDS) in addition to the National Center for Research Resources CTSA grants UL1RR025750, KL2RR025749 and TL1RR025748, and from the National Institute of Allergy and Infectious Diseases grant R01A1052065 (AAK). Clinical data and specimens used in this study were collected by the Women’s Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (KA); Brooklyn, NY (HM); Washington DC, Metropolitan Consortium (MY); The Connie Wofsy Study Consortium of Northern California (RG); Los Angeles County/Southern California Consortium (AL); Chicago Consortium (MC); Data Coordinating Center (SG). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993 and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI grant number UL1 RR024131). This project has also been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, the National Institutes of Health under Contract No. HHSN261200800001E. This research was also supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research and by the Einstein–Montefiore Center for AIDS Research (5P30AI051519-08).

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Authors and Affiliations

  1. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

    M H Kuniholm, K Anastos, X Xue & H D Strickler

  2. Department of Medicine, Montefiore Medical Center, Bronx, NY, USA

    K Anastos

  3. Department of Pediatrics, University of Southern California, Los Angeles, CA, USA

    A Kovacs

  4. Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    X Gao, D Marti & M Carrington

  5. Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA

    X Gao, D Marti & M Carrington

  6. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA

    A Sette

  7. Department of Clinical Pharmacy, University of California, San Francisco, CA, USA

    R M Greenblatt

  8. Department of Medicine, University of California, San Francisco, CA, USA

    M Peters

  9. CORE Center, Cook County Bureau of Health Services, Chicago, IL, USA

    M H Cohen

  10. Department of Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, NY, USA

    H Minkoff

  11. Department of Epidemiology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    S J Gange

  12. Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    C L Thio

  13. Department of Medicine, Georgetown University Medical Center, Washington, DC, USA

    M A Young

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  1. M H Kuniholm
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Correspondence to M H Kuniholm.

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Kuniholm, M., Anastos, K., Kovacs, A. et al. Relation of HLA class I and II supertypes with spontaneous clearance of hepatitis C virus. Genes Immun 14, 330–335 (2013). https://doi.org/10.1038/gene.2013.25

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