Mutation Hot Spots in Hepatitis B Surface Antigen in Chronic Carriers from Khoozestan Province, Southern of Iran
-
Fatemeh Ramezani
,
Mehdi Norouzi
,
Gholam Reza Sarizade
,
Vahdat Poortahmasebi
,
Ebrahim Kalantar
,
Lars Magnius
,
Helen Norder
,
Esteban Domingo
,
Seyed Mohammad Jazayeri
Abstract
Mutations in the human hepatitis B virus (HBV) genome contribute to its escape from host immune surveillance and result in persistent infections. The aim of this study was to characterize the molecular variations of the surface gene and protein in chronically-infected patients from the southern part of Iran.
The surface genes from 12 HBV chronic carriers were amplified, sequenced and subsequently aligned using international and national Iranian database.
All strains belonged to genotype D, subgenotype D1 and subtype ayw2. Of all 30 muta-tions occurred at 22 nucleotide positions, 18 (60%) were missense (amino acid altering) and 12 (40%) were silent (no amino acid changing). The mean mutation frequency (missense to silent nucleotide ratio), was 1.5, indicating application of a high positive selection pressure on the surface proteins. At the amino acid level, of 17 substitutions, 15 (88%) occurred in different immune epitopes within surface protein, of which 7 (46.6%) in B cell epitopes in 5 residues; 7 (46.6%) in T helper epitopes in 6 positions; 1 (7%) in inside CTL epitopes in 1 residue.
We therefore conclude that the distribution of 93.2% of amino acid mutations inside B and T helper immune epitopes as well as the ratio between silent and missense nucleotide mutations showed a positive, focused immune selection pressure on the surface protein, which led to the evolution and emergence of escape mutants in these patients.
1. Alter MJ. Epidemiology and prevention of hepatitis B.Semin liver dis 2003; 23(1):39-46.
2. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012; 30(12):2212-9.
3. Brown SE, Howard CR, Zuckerman AJ, Steward MW.Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides. Lancet 1984;2(8396):184-7.
4. Wallace L, Carman WF. Surface gene variation of HBV:scientific and medical relevance. Viral Hepatitis Rev 1997; 3:5-16.
5. Ducos J, Bianchi-Mondain AM, Pageaux G, Conge AM, Poncet R, Vendrell JP, et al. Hepatitis B virus (HBV)- specific in vitro antibody production by peripheral blood mononuclear cells (PBMC) after vaccination by recombinant hepatitis B surface antigen (rHBsAg). Clin Exp Immunol 1996; 103(1):15-8.
6. Mancini-Bourgine M, Fontaine H, Brechot C, Pol S,Michel ML. Immunogenicity of a hepatitis B DNA vaccine administered to chronic HBV carriers. Vaccine 2006;24(21):4482-9.
7. Min WP, Kamikawaji N, Mineta M, Tana T, Kashiwagi S, Sasazuki T. Identification of an epitope for T-cells correlated with antibody response to hepatitis B surface antigen in vaccinated humans. Hum Immunol 1996;46(2):93-9.
8. Yamamoto K, Horikita M, Tsuda F, Itoh K, Akahane Y, Yotsumoto S, et al. Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen. J Virol 1994; 68(4):2671-6.
9. Avellon A, Echevarria JM. Frequency of hepatitis B virus 'a' determinant variants in unselected Spanish chronic carriers. J Med Virol 2006; 78(1):24-36.
10. Sayad B, Anvari FA, Alavian SM, Norouzi M, Hamzelooie M, Shirvani M, et al. Correlation of Hepatitis B surface antigen mutations with clinical status of the chronically infected patients from Kermanshah, West of Iran. Minerva Gastroenterol Dietol 2012; 58(1):9-18.
11. Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, et al. Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. The J Gen Virol 1988; 69( Pt 10):2575-83.
12. Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 2007; 24(8):1596-9.
13. Jazayeri M, Basuni AA, Sran N, Gish R, Cooksley G, Locarnini S, et al. HBV core sequence: definition of genotype-specific variability and correlation with geographical origin. J Viral Hepat 2004; 11(6):488-501.
14. Jazayeri S, WF Carman. Evolution of hepatitis B genotype D in the Middle east and South Asia. Hep Mon 2009; 9(1):3.
15. Chen M, Sallberg M, Thung SN, Hughes J, Jones J, Milich DR. Modeling the T-helper cell response in acute and chronic hepatitis B virus infection using T-cell receptor transgenic mice. Antiviral res 2001; 52(2):99-111.
16. Khakoo SI, Ling R, Scott I, Dodi AI, Harrison TJ, Dusheiko GM, et al. Cytotoxic T lymphocyte responses and CTL epitope escape mutation in HBsAg, anti-HBe positive individuals. Gut 2000; 47(1):137-43.
17. Liu CJ, Kao JH, Shau WY, Chen PJ, Lai MY, Chen DS.Naturally occurring hepatitis B surface gene variants in chronic hepatitis B virus infection: correlation with viral serotypes and clinical stages of liver disease. J Med Virol 2002; 68(1):50-9.
18. Carman WF, Boner W, Fattovich G, Colman K, Dornan ES, Thursz M, et al. Hepatitis B virus core protein mutations are concentrated in B cell epitopes in progressive disease and in T helper cell epitopes during clinical remission. J Infect Dis 1997; 175(5):1093-100.
19. Carman WF, Thursz M, Hadziyannis S, McIntyre G, Colman K, Gioustoz A, et al. Hepatitis B e antigen negative chronic active hepatitis: hepatitis B virus core mutations occur predominantly in known antigenic determinants. J Viral Hepat 1995; 2(2):77-84.
20. Hosono S, Tai PC, Wang W, Ambrose M, Hwang DG, Yuan TT, et al. Core antigen mutations of human hepatitis B virus in hepatomas accumulate in MHC class II-restricted T cell epitopes. Virology 1995; 212(1):151-62.
21. Yamauchi K, Nakamura T, Yonemitsu H, Sekiya H, Katoh J, Obata H. Possible role of preS2 peptides presented by MHC class I antigen in the pathogenesis of chronic hepatitis B. J Hepatol 1993; 17 Suppl 3:S6-9.
22. Jazayeri SM, Dornan ES, Boner W, Fattovich G,Hadziyannis S, Carman WF. Intracellular distribution of hepatitis B virus core protein expressed in vitro depends on the sequence of the isolate and the serologic pattern. J Infect Dis 2004; 189(9):1634-45.
23. Bauer T, Weinberger K, Jilg W. Variants of two major T cell epitopes within the hepatitis B surface antigen are not recognized by specific T helper cells of vaccinated individuals. Hepatology 2002; 35(2):455-65.
24. Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol 1995; 13:29-60.
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| Issue | Vol 12, No 3 (2013) | |
| Section | Articles | |
| Keywords | ||
| Chronic HBV HBV escape mutations HBV immune epitope HBsAg mutation. | ||
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