Dominant mutations of hepatitis B virus variants in hepatoma accumulate in B-cell and T-cell epitopes of the HBx antigen

Hwang, Guang-Yuh; Huang, Chengming; Lin, Chuang-Yu; Wu, Chien-Hung

doi:10.1016/s0168-1702(03)00043-1

Cited by 14 publications

(13 citation statements)

References 43 publications

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“…Although we observed sequence heterogeneity in CTL epitopes of HBV/D, no statistically significant association was found with any disease state. In hepatoma patients of Taiwan, where HBV/B and C prevail, dominant mutations were detected within regions of aa 26–45 in the B‐cell epitope and 116–127 in the T‐cell epitope in HBx [20]. In contrast, our results indicated that variations in HBx were most pronounced at aa 46 and 47 in the B‐cell epitope and at 102 in the T H epitope and occurred most frequently among LC.…”

Section: Discussionmentioning

confidence: 65%

Tracking the naturally occurring mutations across the full-length genome of hepatitis B virus of genotype D in different phases of chronic e-antigen-negative infection

Ghosh

Mondal

Banerjee

et al. 2012

Clinical Microbiology and Infection

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Clin Microbiol Infect 2012; 18: E412–E418 Abstract Hepatitis B e‐antigen (HBeAg)‐negative chronic HBV infection is highly prevalent in several parts of the world, including India, with the clinical spectrum ranging from inactive carrier (IC) state to chronic ‘e‐negative’ hepatitis B (CHB) and culminating in advanced liver disease such as cirrhosis (LC). The present study has for the first time investigated the natural diversity of HBV belonging to genotype D in treatment‐naïve Indian patients representing the above phases of HBeAg‐negative infection to identify candidate mutations associated with each disease state. Studies of full‐length HBV/D sequences revealed that the progressive accumulation and persistence of mutations in basal core promoter, negative regulatory element, Pre‐core region, the B‐ and T‐cell epitopes of X protein as well as deletions in the PreS region contribute significantly to disease progression from IC through CHB to LC. In addition, the development of CHB was associated with a significant increase in viral variants characterized by mutations in enhancer II, preS1 promoter, T‐cell epitope of core and B‐cell epitope region of PreS1. While few of the mutations were previously reported in the context of HBV genotypes B and C, others had not been documented before. Our results thus highlight a distinct pattern of mutation in HBV/D that may help in predicting clinical outcomes of HBeAg‐negative infection and have implications for better clinical management of the patients.

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Section: Discussionmentioning

confidence: 65%

Tracking the naturally occurring mutations across the full-length genome of hepatitis B virus of genotype D in different phases of chronic e-antigen-negative infection

Ghosh

Mondal

Banerjee

et al. 2012

Clinical Microbiology and Infection

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show abstract

“…For all HBV ORFs, pairwise estimates of the number of synonymous substitutions/synonymous site (d S ) and the number of non-synonymous substitutions/non-synonymous site (d N ) were computed using a modified Nei-Gojobori model with Jukes-Cantor correction as implemented in MEGA5. Values of d S and d N were estimated for all published Tc-, Thand B-cell epitopes of HBV [2,[10][11][12], along with overlapping epitope and non-epitope regions. HBV sequence variability in different patient groups was analysed with the help of multiple alignment data.…”

Section: Sequence Analysismentioning

confidence: 99%

Immune-driven adaptation of hepatitis B virus genotype D involves preferential alteration in B-cell epitopes and replicative attenuation—an insight from human immunodeficiency virus/hepatitis B virus coinfection

Mondal

Khatun

Ghosh

et al. 2015

Clinical Microbiology and Infection

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An important driving force behind the sequence diversity of hepatitis B virus (HBV) is viral adaptation to host immune responses. To gain an insight into the impact of host immunity on genetic diversification and properties of HBV, we characterized HBV of genotype D from treatment-naive hepatitis B e antigen-positive (EP) and hepatitis B e antigen-negative (EN) patients with chronic hepatitis B (CHB), where HBV is under stronger immune pressure, with that of HBV derived from human immunodeficiency virus (HIV)/HBV-coinfected individuals, where HIV infection has significantly weakened the immune system. Full-length sequence analysis showed that HBV heterogeneity was most extensive in EN-CHB followed by EP-CHB and HIV/HBV coinfection. The relative magnitude of non-synonymous changes within B-cell epitopes was greater than that in T-cell epitopes of HBV open reading frames (ORFs) in both EP-CHB and EN-CHB. Nine amino acid substitutions were identified in B-cell epitopes and one in a T-cell epitope of HBV in EN-CHB, most of which resulted in altered hydrophobicities, as determined using the Kyte and Doolittle method, relative to wild-type residues found in HBV from the HIV-positive group. Additionally, 19 substitutions occurred at significantly higher frequencies in non-epitope regions of HBV ORF-P in EN-CHB than HIV/HBV-coinfected patients. In vitro replication assay demonstrated that the substitutions, particularly in reverse transcriptase and RNaseH domains of ORF-P, resulted in a decline in replication capacity of HBV. Hence, our results indicate that HBV adapts to increasing immune pressure through preferential mutations in B-cell epitopes and by replicative attenuation. The viral epitopes linked to immune response identified in this study bear important implications for future HBV vaccine studies.

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“…The most frequent variants of HBV x gene isolated from hepatocellular carcinoma patients were located in the B-or T-cell epitopes (Hwang et al, 2003). On the other hand, the studies on HPV-16 E6 variants showed the most common variation isolated from cervical cancer patients was T to G at nucleotide position 350 (Brady et al, 1999;Hu et al, 1999).…”

Section: Introductionmentioning

confidence: 98%

“…Studies on viral variants revealed that variants may rise the opportunity for reinfection or evasion from host immune system, like influenza virus and hepatitis B virus (Ferguson et al, 2003 and references there in;Hwang et al, 2003). The most frequent variants of HBV x gene isolated from hepatocellular carcinoma patients were located in the B-or T-cell epitopes (Hwang et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The prevalence of HPV-18 and variants of E6 gene isolated from cervical cancer patients in Taiwan

Chang

Chen

Hsu

et al. 2005

Journal of Clinical Virology

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Dominant mutations of hepatitis B virus variants in hepatoma accumulate in B-cell and T-cell epitopes of the HBx antigen

Cited by 14 publications

References 43 publications

Tracking the naturally occurring mutations across the full-length genome of hepatitis B virus of genotype D in different phases of chronic e-antigen-negative infection

Tracking the naturally occurring mutations across the full-length genome of hepatitis B virus of genotype D in different phases of chronic e-antigen-negative infection

Immune-driven adaptation of hepatitis B virus genotype D involves preferential alteration in B-cell epitopes and replicative attenuation—an insight from human immunodeficiency virus/hepatitis B virus coinfection

The prevalence of HPV-18 and variants of E6 gene isolated from cervical cancer patients in Taiwan

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