Spontaneous HBsAg loss in Korean patients: relevance of viral genotypes, S gene mutations, and covalently closed circular DNA copy numbers
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Background/Aims: Occult HBV infection can persist following HBsAg loss and be transmitted, but the virologicalfeatures are not well defined. Methods: Here we investigated 25 Korean patients who lost HBsAg during follow up, either spontaneously orsubsequent to therapy. Results: Whereas subtype adr (genotype C) was found in 96% of HBsAg positive patients, 75 % of patients wholost HBsAg spontaneously were seemed to be infected with the ayw subtype with sequence similar to genotype D. Mutations in the major hydrophilic region (MHR) of HBsAg were found in 7 patients who lost HBsAg spontaneously. The mutations include T123S, M125I/N, C139R, D144E, V177A, L192F, and W196L, some of which have not been reportedbefore. Functional analysis via transfection experiments indicate that the C139R and D144E mutations drastically reducedHBsAg antigenicity, while the Y225del mutation found in one interferon-treated patient impaired HBsAg secretion. Conclusions: Lack of detectable HBsAg in patient serum could be explained by low level of ccc DNA in liver tissue, lowantigenicity of the surface protein, or its secretion defect.
Abstract
Background/Aims: Occult HBV infection can persist following HBsAg loss and be transmitted, but the virologicalfeatures are not well defined. Methods: Here we investigated 25 Korean patients who lost HBsAg during follow up, either spontaneously orsubsequent to therapy. Results: Whereas subtype adr (genotype C) was found in 96% of HBsAg positive patients, 75 % of patients wholost HBsAg spontaneously were seemed to be infected with the ayw subtype with sequence similar to genotype D. Mutations in the major hydrophilic region (MHR) of HBsAg were found in 7 patients who lost HBsAg spontaneously. The mutations include T123S, M125I/N, C139R, D144E, V177A, L192F, and W196L, some of which have not been reportedbefore. Functional analysis via transfection experiments indicate that the C139R and D144E mutations drastically reducedHBsAg antigenicity, while the Y225del mutation found in one interferon-treated patient impaired HBsAg secretion. Conclusions: Lack of detectable HBsAg in patient serum could be explained by low level of ccc DNA in liver tissue, lowantigenicity of the surface protein, or its secretion defect.
참고문헌 (38)
- Raimondo G, "Occult hepatitis B virus infection", J Hepatol, 46, pp.160~170 (2007)
- Wong DK, "Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma", Hepatology, 54, pp.829~836 (2011)
- Pollicino T, "Occult hepatitis B virus and hepatocellular carcinoma", World J Gastroenterol, 20, pp.5951~5961 (2014)
- Chazouilleres O, "“Occult” hepatitis B virus as source of infection in liver transplant recipients", Lancet, d343 (1994)
- Blackberg J, "Occult hepatitis B virus after acute self-limited infection persisting for 30 years without sequence variation", J Hepatol, 33, pp.992~997 (2000)
- Brechot C, "Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely “occult”?", Hepatology, 34, pp.194~203 (2001)
- Loriot MA, "Persistence of hepatitis B virus DNA in serum and liver from patients with chronic hepatitis B after loss of HBsAg", J Hepatol, 27, pp.251~258 (1997)
- Huang X, "Occult hepatitis B virus infection and hepatocellular carcinoma: a systematic review", J Viral Hepat, 21, pp.153~162 (2014)
- Bréchot C, "Hepatitis B virus DNA in patients with chronic liver disease and negative tests for hepatitis B surface antigen", N Engl J Med, 312, pp.270~276 (1985)
- Hou J, "Prevalence of naturally occurring surface gene variants of hepatitis B virus in nonimmunized surface antigen-negative Chinese carriers", Hepatology, 34, pp.1027~1034 (2001)
- Yamamoto K, "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, 68, pp.2671~2676 (1994)
- Kato J, "A molecular analysis of viral persistence in surface antigen–negative chronic hepatitis B", Hepatology, 23, pp.389~395 (1996)
- Carman WF, "The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia", Hepatology, 26, pp.1658~1666 (1997)
- Carman WF, "Fulminant reactivation of hepatitis B due to envelope protein mutant that escaped detection by monoclonal HBsAg ELISA", Lancet, 345, pp.1406~1407 (1995)
- Pollicino T, "Hepatitis b virus PreS", S gene variants: pathobiology and clinical implications, 2014, pp.61, 408~417
- Cacciola I, "Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease", N Engl J Med, 341, pp.22~26 (1999)
- 장재영, "Clinical significance of occult hepatitis B virus infection in chronic hepatitis C patients", Clinical and Molecular Hepatology, 17(3), pp.206~212 (2011), 대한간학회
- Hofer M, "Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Swiss HIV Cohort Study", Eur J Clin Microbiol Infect Dis, 17, pp.6~13 (1998)
- Tuttleman JS, "Formation of the pool of cova lently closed circular viral DNA in hepadnavirus-infected cells", Cell, 47, pp.451~460 (1986)
- Kim KH, "Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal", EMBO J, 22, pp.2104~2116 (2003)
- Dereeper A, "Phylogeny.fr: robust phylogenetic analysis for the non-specialist", Nucleic Acids Res, 36, pp.w465~w469 (2008)
- He ML, "A new and sensitive method for the quantification of HBV cccDNA by real-time PCR", Biochem Biophys Res Commun, 295, pp.1102~1107 (2002)
- Min CH, "Subtypes of hepatitis B surface antigen in Korea in comparison with other Asian nations", J Korean Soc Microbiol, 26, pp.289~299
- Usuda S, "Serological detection of hepatitis B virus genotypes by ELISA with monoclonal antibodies to type-specific epitopes in the preS2-region product", J Virol Methods, 80, pp.97~112 (1999)
- Norder H, "Genetic relatedness of hepatitis B viral strains of diverse geographical origin and natural variations in the primary structure of the surface antigen", J Gen Virol, 74, pp.1341~1348 (1993)
- Furusyo N, "Hepatitis B surface antigen disappearance and hepatitis B surface antigen subtype: a prospective, long-term, follow-up study of Japanese residents of Okinawa, Japan with chronic hepatitis B virus infection", Am J Trop Med Hyg, 60, pp.616~622 (1999)
- Bahn A, "Detection of different viral strains of hepatitis B virus in chronically infected children after seroconversion from HBsAg to anti-HBs indicating viral persistence", J Hepatol, 27, pp.973~978 (1997)
- Mangold CM, "Secretion and antigenicity of hepatitis B virus small envelope proteins lacking cysteines in the major antigenic region", Virology, 211, pp.535~543 (1995)
- Mangold CM, "Mutational analysis of the cysteine residues in the hepatitis B virus small envelope protein", J Virol, 67, pp.4588~4597 (1993)
- Protzer-Knolle U1, "Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation", Hepatology, 27, pp.254~263 (1998)
- Ijaz S, "Novel immunoassay for the detection of hepatitis B surface ‘escape’ mutants and its application in liver transplant recipients", J Med Virol, 63, pp.210~216 (2001)
- Ghany MG, "Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis", Hepatology, 27, pp.213~222 (1998)
- Terrault NA, "Incidence and clinical consequences of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin", Hepatology, 28, pp.555~561 (1998)
- Kim KH, "Evolution of hepatitis B virus sequence from a liver transplant recipient with rapid breakthrough despite hepatitis B immune globulin prophylaxis and lamivudine therapy", J Med Virol, 71, pp.367~375 (2003)
- Kalinina T, "A dominant hepatitis B virus population defective in virus secretion because of several Sgene mutations from a patient with fulminant hepatitis", Hepatology, 34, pp.385~394 (2001)
- Khan N, "Modulation of hepatitis B virus secretion by naturally occurring mutations in the S gene", J Virol, 78, pp.3262~3270 (2004)
- Ahn SH, "The impact of the hepatitis B virus polymerase rtA181T mutation on replication and drug resistance is potentially affected by overlapping changes in surface gene", J Virol, 88, pp.6805~6818 (2014)
- Zanella I, "Real-time quantitation of hepatitis B virus (HBV) DNA in tumorous and surrounding tissue from patients with hepatocellular carcinoma", J Med Virol, 68, pp.494~499 (2002)