Reduced Expression of DNA Damage Repair Genes High Mobility Group Box1 and Poly(ADP-ribose) Polymerase1 in Inactive Carriers of Hepatitis B Virus Infection-A Possible Stage of Viral Integration

Background High mobility group box1 (HMGB1) and poly(ADP-ribose) polymerase1 (PARP1) proteins repair cellular DNA damage. Reduced expression of the corresponding genes can lead to an impaired DNA damage repair mechanism. Intracellular replication of hepatitis B virus (HBV) in such conditions can fav...

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Published in:	Journal of clinical and experimental hepatology Vol. 3; no. 2; pp. 89 - 95
Main Authors:	Mukherjee, Rathindra M, Shravanti, Gelli V, Jakkampudi, Aparna, Kota, Ramya, Jangala, Asha L, Reddy, Panyala B, Rao, Padaki N, Gupta, Rajesh, Reddy, Duvvuru N
Format:	Journal Article
Language:	English
Published:	India Elsevier B.V 01-06-2013 Elsevier
Subjects:	Endocrinology & Metabolism Gastroenterology and Hepatology gene expression hepatitis B virus high mobility group box1 Original poly(ADP-ribose) polymerase1 pregenomic RNA hepatitis B virus e antigen cccDNA hepatitis B virus ALT acute hepatitis B HMGB1 ADP hepatitis E virus Child–Pugh RT-PCR adenosine diphosphate double stranded HBV DNA PgRNA IC deoxynucleoside triphosphates pregenomic RNA HBV hepatocellular carcinoma HBX PARP1 reverse transcription PCR HBeAg base excision repair HCC HBsAg DEPC unique integration sites CIRRH hepatitis B virus X protein UISs human immunodeficiency virus gene expression poly(ADP-ribose) polymerase1 PCR dsDNA covalently closed circular DNA ELISA standard deviation DTT IgG moloney murine leukemia virus Rnase H alanine transferase IgM inactive carriers aspartate transferase SD rcDNA hepatitis B virus surface antigen HDV polymerase chain reaction cirrhosis hepatitis delta virus peripheral blood mononuclear cells chronic HBV AST immunoglobulin G diethyl pyrocarbonate dithiothreitol immunoglobulin M dNTPs high mobility group box1 PBMCs CP BER hepatitis A virus HIV MuLV-H enzyme-linked immunosorbent assay HEV NER AHB CHB HAV relaxed circular DNA nucleotide excision repair HBV, hepatitis B virus HAV, hepatitis A virus dsDNA, double stranded HBV DNA HDV, hepatitis delta virus ELISA, enzyme-linked immunosorbent assay MuLV-H, moloney murine leukemia virus Rnase H DTT, dithiothreitol HBsAg, hepatitis B virus surface antigen RT-PCR, reverse transcription PCR HEV, hepatitis E virus SD, standard deviation PBMCs, peripheral blood mononuclear cells CHB, chronic HBV CP, Child–Pugh HBeAg, hepatitis B virus e antigen DEPC, diethyl pyrocarbonate IgM, immunoglobulin M AST, aspartate transferase HIV, human immunodeficiency virus BER, base excision repair PARP1, poly(ADP-ribose) polymerase1 PgRNA, pregenomic RNA ALT, alanine transferase dNTPs, deoxynucleoside triphosphates IgG, immunoglobulin G AHB, acute hepatitis B NER, nucleotide excision repair HBX, hepatitis B virus X protein UISs, unique integration sites HMGB1, high mobility group box1 ADP, adenosine diphosphate CIRRH, cirrhosis PCR, polymerase chain reaction HCC, hepatocellular carcinoma IC, inactive carriers cccDNA, covalently closed circular DNA rcDNA, relaxed circular DNA
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Summary:	Background High mobility group box1 (HMGB1) and poly(ADP-ribose) polymerase1 (PARP1) proteins repair cellular DNA damage. Reduced expression of the corresponding genes can lead to an impaired DNA damage repair mechanism. Intracellular replication of hepatitis B virus (HBV) in such conditions can favor the integration of viral DNA into host genome leading to the development of hepatocellular carcinoma (HCC). Objective This study was performed to assess the expression of HMGB1 and PARP1 mRNAs in conjunction with the estimation of HBV replication intermediate pregenomic RNA (PgRNA) in various phases of HBV infection. Materials Eighty eight patients and 26 voluntary blood donors as controls were included in the study. Patients were grouped in to acute (AHB; n = 15), inactive carriers (IC; n = 36), cirrhosis (Cirr; n = 25) and hepatocellular carcinoma (HCC; n = 12). Serum HBV DNA was quantified by real time polymerase chain reaction (PCR) assay. Expression of HMGB1, PARP1 and PgRNA were evaluated using peripheral blood mononuclear cells (PBMCs) derived RNA by reverse transcription PCR (RT-PCR) and densitometry. Results Significant reduction of HMGB1 and PARP1 gene expressions ( P < 0.05) were observed in patients than controls with more explicit decline of PARP1 ( P = 0.0002). Both genes were significantly downregulated ( P < 0.001) in ICs than controls. In ICs, HMGB1 was significantly lowered than cirrhosis ( P = 0.002) and HCC ( P = 0.0006) while PARP1 declined significantly ( P = 0.04) than HCC. Level of PgRNA was comparable in all the disease categories. Conclusion In conclusion, our findings indicate impaired DNA damage repair mechanisms in HBV infected cells of ICs. This, along with low viral load but higher level of PgRNA in this group is suggestive of the diversion of HBV replication pathway that might facilitate viral DNA integration in to host genome. Intrusion of HBV PgRNA reverse transcription in early stage of infection might appear advantageous to thwart the development of HCC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0973-6883 2213-3453
DOI:	10.1016/j.jceh.2013.04.003