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CCR5-Δ32 genotype does not improve predictive value of IL28B polymorphisms for treatment response in chronic HCV infection

Genes & Immunity volume 14, pages 286–290 (2013)Cite this article

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Abstract

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.

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References

  1. WHOHepatitis C. Fact Sheet No. 164. Revised October 2000. http://www.who.int/mediacentre/factsheets/fs164/en/.

  2. Hoofnagle JH . Course and outcome of hepatitis C. Hepatology 2002; 36: S21–S29.

    Google Scholar 

  3. Lambotin M, Raghuraman S, Stoll-Keller F, Baumert TF, Barth H . A look behind closed doors: interaction of persistent viruses with dendritic cells. Nat Rev Microbiol 2010; 8: 350–360.

    Article  CAS  Google Scholar 

  4. Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH . Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999; 163: 6236–6243.

    CAS  PubMed  Google Scholar 

  5. Soo HM, Garzino-Demo A, Hong W, Tan YH, Tan YJ, Goh PY et al. Expression of a full-length hepatitis C virus cDNA up-regulates the expression of CC chemokines MCP-1 and RANTES. Virology 2002; 303: 253–277.

    Article  CAS  Google Scholar 

  6. Nattermann J, Nischalke HD, Feldmann G, Ahlenstiel G, Sauerbruch T, Spengler U . Binding of HCV E2 to CD81 induces RANTES secretion and internalization of CC chemokine receptor 5. J Viral Hepat 2004; 11: 519–526.

    Article  CAS  Google Scholar 

  7. Lichterfeld M, Leifeld L, Nischalke HD, Rockstroh JK, Hess L, Sauerbruch T et al. Reduced CC chemokine receptor (CCR) 1 and CCR5 surface expression on peripheral blood T lymphocytes from patients with chronic hepatitis C infection. J Infect Dis 2002; 185: 1803–1807.

    Article  CAS  Google Scholar 

  8. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996; 381: 661–666.

    Article  CAS  Google Scholar 

  9. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382: 722–725.

    Article  CAS  Google Scholar 

  10. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996; 273: 1856–1862.

    Article  CAS  Google Scholar 

  11. Stewart G . Chemokine genes--beating the odds. Nat Med 1998; 4: 275–257.

    Article  CAS  Google Scholar 

  12. Woitas RP, Ahlenstiel G, Iwan A, Rockstroh JK, Brackmann HH, Kupfer B et al. Frequency of the HIV-protective CC chemokine receptor 5-Delta32/Delta32 genotype is increased in hepatitis C. Gastroenterology 2002; 122: 1721–1728.

    Article  CAS  Google Scholar 

  13. Goulding C, McManus R, Murphy A, MacDonald G, Barrett S, Crowe J et al. The CCR5-delta32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source. Gut 2005; 54: 1157–1161.

    Article  CAS  Google Scholar 

  14. Nattermann J, Timm J, Nischalke HD, Olbrich A, Michalk M, Tillmann HL et al. The predictive value of IL28B gene polymorphism for spontaneous clearance in a single source outbreak cohort is limited in patients carrying the CCR5Delta32 mutation. J Hepatol 2011; 55: 1201–1206.

    Article  CAS  Google Scholar 

  15. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461: 798–801.

    Article  CAS  Google Scholar 

  16. Suppiah V, Gaudieri S, Armstrong NJ, O'Connor KS, Berg T, Weltman M et al. IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European cohort: a cross-sectional study. PLoS Med 2011; 8: e1001092.

    Article  CAS  Google Scholar 

  17. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.

    Article  CAS  Google Scholar 

  18. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009; 41: 1100–1104.

    Article  CAS  Google Scholar 

  19. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41: 1105–1109.

    Article  CAS  Google Scholar 

  20. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138: 1338–1345.

    Article  CAS  Google Scholar 

  21. Ahlenstiel G, Berg T, Woitas RP, Grunhage F, Iwan A, Hess L et al. Effects of the CCR5-Delta32 mutation on antiviral treatment in chronic hepatitis C. J Hepatol 2003; 39: 245–252.

    Article  CAS  Google Scholar 

  22. Promrat K, McDermott DH, Gonzalez CM, Kleiner DE, Koziol DE, Lessie M et al. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C. Gastroenterology 2003; 124: 352–360.

    Article  CAS  Google Scholar 

  23. Hellier S, Frodsham AJ, Hennig BJ, Klenerman P, Knapp S, Ramaley P et al. Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection. Hepatology 2003; 38: 1468–1476.

    Article  CAS  Google Scholar 

  24. Mascheretti S, Hinrichsen H, Ross S, Buggisch P, Hampe J, Foelsch UR et al. Genetic variants in the CCR gene cluster and spontaneous viral elimination in hepatitis C-infected patients. Clin Exp Immunol 2004; 136: 328–333.

    Article  CAS  Google Scholar 

  25. Wasmuth HE, Werth A, Mueller T, Berg T, Dietrich CG, Geier A et al. CC chemokine receptor 5 delta32 polymorphism in two independent cohorts of hepatitis C virus infected patients without hemophilia. J Mol Med 2004; 82: 64–69.

    Article  CAS  Google Scholar 

  26. Goyal A, Suneetha PV, Kumar GT, Shukla DK, Arora N, Sarin SK . CCR5Delta32 mutation does not influence the susceptibility to HCV infection, severity of liver disease and response to therapy in patients with chronic hepatitis C. World J Gastroenterol 2006; 12: 4721–4726.

    Article  CAS  Google Scholar 

  27. Glas J, Torok HP, Simperl C, Konig A, Martin K, Schmidt F et al. The delta 32 mutation of the chemokine-receptor 5 gene neither is correlated with chronic hepatitis C nor does it predict response to therapy with interferon-alpha and ribavirin. Clin Immunol 2003; 108: 46–50.

    Article  CAS  Google Scholar 

  28. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–982.

    Article  CAS  Google Scholar 

  29. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346–355.

    Article  CAS  Google Scholar 

  30. Novembre J, Galvani AP, Slatkin M . The geographic spread of the CCR5 Delta32 HIV-resistance allele. PLoS Biol 2005; 3: e339.

    Article  Google Scholar 

  31. Shin EC, Seifert U, Kato T, Rice CM, Feinstone SM, Kloetzel PM et al. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J Clin Invest 2006; 116: 3006–3014.

    Article  CAS  Google Scholar 

  32. Yang YF, Tomura M, Iwasaki M, Ono S, Zou JP, Uno K et al. IFN-alpha acts on T-cell receptor-triggered human peripheral leukocytes to up-regulate CCR5 expression on CD4+ and CD8+ T cells. J Clin Immunol 2001; 21: 402–429.

    Article  CAS  Google Scholar 

  33. Thomas E, Feld JJ, Li Q, Hu Z, Fried MW, Liang TJ . Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models. Hepatology 2001; 53: 32–41.

    Article  Google Scholar 

  34. Tam RC, Pai B, Bard J, Lim C, Averett DR, Phan U et al. Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J Hepatol 1999; 30: 376–382.

    Article  CAS  Google Scholar 

  35. Ahlenstiel G, Booth DR, Goerge J . Will IL28B polymorphism remain relevant to DAA treatment paradigms? Antiviral Therapy 2012; 17 (6 Pt B): 1163–1170.

    Article  CAS  Google Scholar 

  36. Fatkenheuer G, Hoffmann C, Slim J, Rouzier R, Keung A, Li J et al. Short-term administration of the CCR5 antagonist vicriviroc to patients with HIV and HCV coinfection is safe and tolerable. J Acquir Immune Defic Syndr 2010; 53: 78–85.

    Article  Google Scholar 

  37. Bennetts BH, Teutsch SM, Buhler MM, Heard RN, Stewart GJ . The CCR5 deletion mutation fails to protect against multiple sclerosis. Hum Immunol 1997; 58: 52–59.

    Article  CAS  Google Scholar 

  38. Libert F, Cochaux P, Beckman G, Samson M, Aksenova M, Cao A et al. The deltaccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe. Hum Mol Genet 1998; 7: 399–406.

    Article  CAS  Google Scholar 

  39. Spagnolo P, Renzoni EA, Wells AU, Copley SJ, Desai SR, Sato H et al. C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis. Am J Respir Crit Care Med 2005; 172: 721–728.

    Article  Google Scholar 

  40. Oh DY, Jessen H, Kucherer C, Neumann K, Oh N, Poggensee G et al. CCR5Delta32 genotypes in a German HIV-1 seroconverter cohort and report of HIV-1 infection in a CCR5Delta32 homozygous individual. PLoS One 2008; 3: e2747.

    Article  Google Scholar 

  41. Nischalke HD, Nattermann J, Lichterfeld M, Woitas RP, Rockstroh JK, Sauerbruch T et al. Rapid determination of the Delta32 deletion in the human CC-chemokine receptor 5 (CCR5) gene without DNA extraction by lightcycler real-time polymerase chain reaction. AIDS Res Hum Retroviruses 2004; 20: 750–754.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by research grants from the National Health and Medical Research Council of Australia and by an Australian ARC linkage grant. JG is supported by the Robert W Storr bequest to the University of Sydney Medical Foundation. We thank all patients for their valuable participation in this study. We also thank Reynold Leung for technical assistance.

Author information

Author notes

  1. V Suppiah

    Present address: 18Current address: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.,

Authors and Affiliations

  1. Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia

    V Suppiah, J George & G Ahlenstiel

  2. Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia

    V Suppiah, K S O'Connor, G J Stewart & D R Booth

  3. Cancer Research Program, Garvan Institute for Medical Research, University of New South Wales, Sydney, NSW, Australia

    N J Armstrong

  4. School of Mathematics and Statistics, University of New South Wales, Sydney, NSW, Australia

    N J Armstrong

  5. Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum, Universitätsmedizin, Berlin, Germany

    T Berg & T Mueller

  6. Department of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany

    T Berg & T Mueller

  7. Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia

    M Weltman

  8. Department of Internal Medicine, Liver Physiopathology Lab, University of Turin, Turin, Italy

    M L Abate

  9. Department of Internal Medicine I, University of Bonn, Bonn, Germany

    U Spengler & J Nattermann

  10. Liver Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK

    M Bassendine

  11. The Kirby Institute, University of New South Wales, Sydney, NSW, Australia

    G J Dore

  12. Department of Immunology and Infectious Diseases, St Vincent's Hospital, Sydney, NSW, Australia

    G J Dore

  13. NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, UK

    W L Irving

  14. Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia

    E Powell

  15. The University of Queensland, School of Medicine, Princess Alexandra Hospital, Brisbane, QLD, Australia

    E Powell

  16. Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia

    S Riordan

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Consortia

and the International Hepatitis C Genetics Consortium (IHCGC)

  • Monika Michalk
  • , Barbara Malik
  • , Patrick McClure
  • , Sherie Smith
  • , David Sheridan
  • , Elizabeth Snape
  • , Vincenzo Fragomeli
  • , Richard Norris
  • , Dianne How-Chow
  • , Julie R Jonsson
  • , Helen Barrie
  • , Sacha Stelzer-Braid
  • , Shona Fletcher
  • , Tanya Applegate
  • , Jason Grebely
  • , Gail Matthews
  • , Mandvi Bharadwaj
  •  & Antonina Smedile

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Correspondence to J George.

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Contributors Monika Michalk (University of Bonn, Germany), Barbara Malik (Universitaetsmedizin Berlin, Germany), Patrick McClure (University of Nottingham, UK), Sherie Smith (University of Nottingham, UK), David Sheridan (Newcastle University, UK), Elizabeth Snape (Nepean Hospital, Australia), Vincenzo Fragomeli (Nepean Hospital, Australia), Richard Norris (St Vincent's Hospital, Australia), Dianne How-Chow (St Vincent's Hospital, Australia), Julie R. Jonsson (Princess Alexandra Hospital, Australia), Helen Barrie (Princess Alexandra Hospital, Australia), Sacha Stelzer-Braid (Prince of Wales Hospital, Australia), Shona Fletcher (Prince of Wales Hospital, Australia), Tanya Applegate (National Centre in HIV Epidemiology and Clinical Research), Jason Grebely (National Centre in HIV Epidemiology and Clinical Research), Gail Matthews (National Centre in HIV Epidemiology and Clinical Research), Mandvi Bharadwaj (Burnet Institute, Australia), Antonina Smedile (University of Turin, Italy).

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Suppiah, V., Armstrong, N., O'Connor, K. et al. CCR5-Δ32 genotype does not improve predictive value of IL28B polymorphisms for treatment response in chronic HCV infection. Genes Immun 14, 286–290 (2013). https://doi.org/10.1038/gene.2013.15

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