Single Nucleotide Polymorphisms of Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) and Susceptibility to Chronic Viral Hepatitis B and C Infections

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Moisés Enciso-Vargas
Bertha Ruíz-Madrigal
Zamira Helena Hernández-Nazara
Montserrat Maldonado-González


Cytotoxic T-lymphocyte antigen 4, CTLA-4, Hepatitis C virus, Hepatitis B virus, single nucleotide polymorphisms


The cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is a negative regulator of T-lymphocyte activation and proliferation. Single nucleotide polymorphisms (SNPs) occurring on the CTLA-4 gene can modify the ability to control the proliferation of T-lymphocytes, thereby impacting the clearance of hepatitis B (HBV) and hepatitis C (HCV) virus infections. The −319C/T and +49A/G SNPs of CTLA-4 gene have been associated with autoimmune disorders and liver infections. Studies show that the +49G allele confers susceptibility to HBV and HCV infections in chronic disease (without cirrhosis), associates with the risk of chronic HCV infection in males, confers protective effect against the development of hepatocellular carcinoma, and favors viral elimination. Furthermore, the +49G allele alone or in haplotype with the −319C favors chronic infection with genotype 3 HCV, has an inverse association with HCV genotype 1, and decreases viral load in chronic hepatitis C associated with sustained virological response (SVR). These findings support an important role of the SNPs of CTLA-4 gene in viral hepatitis; however, the mechanisms by which they influence immune response against viral infections are not fully understood. This review gives an overview of the current understanding of the association between CTLA4 SNPs and HBV/HCV infections.


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1. Virgin HW, Wherry EJ, Ahmed R. Redefining chronic viral infection. Cell. 2009 Jul;138(1):30–50.
2. Cox MA, Nechanitzky R, Mak TW. Check point inhibitors as therapies for infectious diseases. Curr Opin Immunol. 2017;48:61–7.
3. Ploss A, Dubuisson J. New advances in the molecular biology of hepatitis C virus infection: Towards the identification of new treatment targets. Gut. 2012 May;61(1):i25–35.
4. Deuffic-Burban S, Mohammed MK, Larouze B, Carrat F, Valleron AJ. Expected increase in hepatitis C-related mortality in Egypt due to pre-2000 infections. J Hepatol. 2006 Mar;44(3):455–61.
5. Williams R. Global challenges in liver disease. Hepatology. 2006 Sep;44(3):521–6.
6. Maddrey WC. Hepatitis B: An important public health issue. J Med Virol. 2000 Jul;61(3):362–6. 61:3%3C362::AID-JMV14%3E3.0.CO;2-I
7. Lee WM. Hepatitis B virus infection. N Engl J Med. 1997 Dec;337(24):1733–45.
8. Ganem D, Prince AM. Hepatitis B virus infection—Natural history and clinical consequences. N Engl J Med. 2004 Mar;350(11):1118–29.
9. Thursz M. Genetic susceptibility in chronic viral hepatitis. Antiviral Res. 2001 Nov;52(2):113–16.
10. Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci. 2006 Apr;3(2):47–52.
11. Restrepo-Gutierre JC, Jaramillo-Aristizábal MC, García-Rendón MV. Serologías en las hepatitis virales. Iatreia. 2011 May;24:76–86.
12. Chisari FV. Cytotoxic T cells and viral hepatitis. J Clin Inves. 1997 Apr;99(7):1472–7.
13. Kim PS, Ahmed R. Features of responding T cells in cancer and chronic infection. Curr Opin Immunol. 2010 Apr;22(2):223–30.
14. Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: A costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–80.
15. June CH, Ledbetter JA, Gillespie MM, Lindsten T, Thompson CB. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol. 1987 Dec;7(12):4472–81.
16. Boise LH, Minn AJ, Noel PJ, June CH, Accavitti MA, Lindsten T, et al. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity. 1995 Jul;3(1):87–98.
17. Brand O, Gough S, Heward J. HLA, CTLA-4 and PTPN22: The shared genetic master-key to autoimmunity? Expert Rev Mol Med. 2005 Oct;7(23):1–15.
18. Dariavach P, Mattei MG, Golstein P, Lefranc MP. Human Ig superfamily CTLA-4 gene: Chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol. 1988 Dec;18(12):1901–5.
19. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002 Jan;16(1):23–35.
20. Appleman LJ, Berezovskaya A, Grass I, Boussiotis VA. CD28 costimulation mediates T cell expansion via IL-2-independent and IL-2-dependent regulation of cell cycle progression. J Immunol. 2000 Jan;164(1):144–51.
21. Scheipers P, Reiser H. Fas-independent death of activated CD4(+) T lymphocytes induced by CTLA-4 crosslinking. Proc Nat Acad Sci U S A. 1998 Aug;95(17):10083–8.
22. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995 Nov;3(5):541–7.
23. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995 Nov 10;270(5238):985–8.
24. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994 Aug;1(5):405–13.
25. Alegre ML, Noel PJ, Eisfelder BJ, Chuang E, Clark MR, Reiner SL, et al. Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J Immunol. 1996 Dec 1;157(11):4762–70.
26. Finn PW, He H, Wang Y, Wang Z, Guan G, Listman J, et al. Synergistic induction of CTLA-4 expression by costimulation with TCR plus CD28 signals mediated by increased transcription and messenger ribonucleic acid stability. J Immunol. 1997 May 1;158(9):4074–81.
27. 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 Dec;38(6):1468–76.
28. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822):860–921.
29. Ghaderi A. CTLA4 gene variants in autoimmunity and cancer: A comparative review. Iran J Immunol. 2011 Sep;8(3):127–49.
30. Enciso-Vargas M, Ruiz-Madrigal B, Munoz-Valle JF, Morales-Balderas OY, Hernandez-Nazara ZH, Martinez-Lopez E, et al. Association of ?319 C/T and +49 A/G polymorphisms of CTLA-4 gene in patients with hepatitis C virus infection. Med Clin. 2017 Oct 12;S0025-7753(17):30658–9.
31. Duan S, Zhang G, Han Q, Li Z, Liu Z, Chen J, et al. CTLA-4 exon 1 +49 polymorphism alone and in a haplotype with ?318 promoter polymorphism may confer susceptibility to chronic HBV infection in Chinese Han patients. Mol Biol Rep. 2011;38(8):5125–32.
32. Thio CL, Mosbruger TL, Kaslow RA, Karp CL, Strathdee SA, Vlahov D, et al. Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection. J Virol. 2004 Oct;78(20):11258–62.
33. Schott E, Witt H, Pascu M, van Boemmel F, Weich V, Bergk A, et al. Association of CTLA4 single nucleotide polymorphisms with viral but not autoimmune liver disease. Eur J Gastroenterol Hepatol. 2007 Nov;19(11):947–51.
34. Gu X, Qi P, Zhou F, Ji Q, Wang H, Dou T, et al. +49G > A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population. Hum Immunol. 2010 Jan;71(1):83–7.
35. National Center for Biotechnology Information (NCBI). [Internet]. 2017 [cited 2017 December 12]. Available from:
36. Mao HT, Wang XB, Zhang L, Gu HT. Studies on the genetic pathogenesis of myasthenia gravis caused by CTLA-4 gene polymorphism. Chin J Med Genet. 2004 Dec;21(6):574–8.
37. Hudson LL, Rocca K, Song YW, Pandey JP. CTLA-4 gene polymorphisms in systemic lupus erythematosus: A highly significant association with a determinant in the promoter region. Human Genet. 2002 Oct;111(4–5):452–5.
38. Wang XB, Zhao X, Giscombe R, Lefvert AK. A CTLA-4 gene polymorphism at position ?318 in the promoter region affects the expression of protein. Genes Immun. 2002 Jun;3(4):233–4.
39. Danilovic DL, Mendes-Correa MC, Lima EU, Zambrini H, K Barros R, Marui S. Correlations of CTLA-4 gene polymorphisms and hepatitis C chronic infection. Liver Int. 2012 May;32(5):803–8.
40. Yee LJ, Perez KA, Tang J, van Leeuwen DJ, Kaslow RA. Association of CTLA4 polymorphisms with sustained response to interferon and ribavirin therapy for chronic hepatitis C virus infection. J Infect Dis. 2003 Apr 15;187(8):1264–71.
41. Khorshied MM, Gouda HM, Khorshid OM. Association of cytotoxic T-lymphocyte antigen 4 genetic polymorphism, hepatitis C viral infection and B-cell non-Hodgkin lymphoma: An Egyptian study. Leuk Lymphoma. 2014 May;55(5):1061–6.
42. Sepahi S, Pasdar A, Gerayli S, Rostami S, Gholoobi A, Meshkat Z. CTLA-4 Gene haplotypes and the risk of chronic hepatitis C infection; a case control study. Rep Biochem Mol Biol. 2017 Oct;6(1):51–8.
43. Chen M, Chang Y, Tang F, Xie QH, Li J, Yang H, et al. Influence of cytotoxic T lymphocyte-associated antigen 4 polymorphisms on the outcomes of hepatitis B virus infection. Mol Med Rep. 2014 Feb;9(2):645–52.
44. Gough SC, Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev. 2005 Apr;204:102–15.
45. Chistiakov DA, Savost’anov KV, Turakulov RI, Efremov IA, Demurov LM. Genetic analysis and functional evaluation of the C/T(?318) and A/G(?1661) polymorphisms of the CTLA-4 gene in patients affected with Graves’ disease. Clin Immunol. 2006 Feb–Mar;118(2–3):233–42.
46. Vaidya B, Pearce SH, Charlton S, Marshall N, Rowan AD, Griffiths ID, et al. An association between the CTLA4 exon 1 polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies. Rheumatology. 2002 Feb;41(2):180–3.
47. Wang XB, Kakoulidou M, Qiu Q, Giscombe R, Huang D, Pirskanen R, et al. CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis. Genes Immunity. 2002 Feb;3(1):46–9.
48. Aguilar F, Torres B, Sanchez-Roman J, Nunez-Roldan A, Gonzalez-Escribano MF. CTLA4 polymorphism in Spanish patients with systemic lupus erythematosus. Hum Immunol. 2003 Oct;64(10):936–40.
49. Maurer M, Loserth S, Kolb-Maurer A, Ponath A, Wiese S, Kruse N, et al. A polymorphism in the human cytotoxic T-lymphocyte antigen 4 ( CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics. 2002 Apr;54(1):1–8.
50. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003 May 29;423(6939):506–11.
51. Anjos S, Nguyen A, Ounissi-Benkalha H, Tessier MC, Polychronakos C. A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J Biol Chem. 2002 Nov 29;277(48):46478–86.
52. Ligers A, Teleshova N, Masterman T, Huang WX, Hillert J. CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun. 2001 May;2(3):145–52.
53. Sun T, Zhou Y, Yang M, Hu Z, Tan W, Han X, et al. Functional genetic variations in cytotoxic T-lymphocyte antigen 4 and susceptibility to multiple types of cancer. Cancer Res. 2008 Sep 1;68(17):7025–34.
54. Matas M, Picornell A, Cifuentes C, Payeras A, Homar F, Gonzalez-Candelas F, et al. Relating the outcome of HCV infection and different host SNP polymorphisms in a Majorcan population coinfected with HCV-HIV and treated with pegIFN-RBV. Int Microbiol. 2014 Mar;17(1):11–20.
55. Lee MH, Yang HI, Yuan Y, L’Italien G, Chen CJ. Epidemiology and natural history of hepatitis C virus infection. World J Gastroenterol. 2014 Jul 28;20(28):9270–80.
56. Sharp A, Robinson D, Jacobs P. Age and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet. 2000 Oct;107(4):343–9.
57. Zhang G, Han Q, Duan S, Li Z, Li N, Zhu Q, et al. PDCD1 polymorphism amplifies the predisposing effect conferred by CTLA4 polymorphism in chronic hepatitis B virus infection. Hum Immunol. 2012 Apr;73(4):421–5.
58. Cheikhrouhou LK, Lakhoua-Gorgi Y, Sfar I, Jendoubi-Ayed S, Aouadi H, Makhlouf M, et al. Natural evolution of HCV infection in hemodialysis Tunisian patients. World J Gastroenterol. 2015 Sep 21;21(35):10150–8.
59. Mohammad Alizadeh AH, Hajilooi M, Ranjbar M, Fallahian F, Mousavi SM. Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to chronic hepatitis B. World J Gastroenterol. 2006 Jan 28;12(4):630–5.
60. Chen DQ, Zeng Y, Zhou J, Yang L, Jiang S, Huang JD, et al. Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese population. J Med Virol. 2010 Mar;82(3):371–8.
61. Xu H, Zhao M, He J, Chen Z. Association between cytotoxic T-lymphocyte associated protein 4 gene +49 A/G polymorphism and chronic infection with hepatitis B virus: A meta-analysis. J Int Med Res. 2013 Jun;41(3):559–67.
62. Murphy DG, Sablon E, Chamberland J, Fournier E, Dandavino R, Tremblay CL. Hepatitis C virus genotype 7, a new genotype originating from central Africa. J Clin Microbiol. 2015 Mar;53(3):967–72.
63. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet. 2001 Sep 22;358(9286):958–65.
64. Rizk HH, Hamdy NM, Al-Ansari NL, El-Mesallamy HO. Pretreatment predictors of response to PegIFN-RBV therapy in Egyptian patients with HCV genotype 4. PLoS One. 2016 Apr 21;11(4):e0153895.
65. Xie Y, Xu DZ, Lu ZM, Luo KX, Jia JD, Wang YM, et al. Predictive factors for sustained response to interferon treatment in patients with chronic hepatitis C: A randomized, open, and multi-center controlled trial. Hepatobiliary Pancreat Dis Int. 2005 May;4(2):213–19.
66. Thompson CB. Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation? Cell. 1995;81(7):979–82.
67. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: The beginning of the end of cancer? BMC Med. 2016 May;14:73.
68. Ravi S, Spencer K, Ruisi M, Ibrahim N, Luke JJ, Thompson JA, et al. Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: A multicenter, retrospective case series. J Immunother Cancer. 2014 Oct 14;2(1):33.
69. Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepato. 2013 Jul;59(1):81–8.