Mutation analyses of integrated HBV genome in hepatitis B patients

Wang, Peilin; Wang, Xiuhai; Cong, Shan; Ma, Hongming; Zhang, Xuecheng

doi:10.1016/s1673-8527(08)60013-2

Cited by 10 publications

(8 citation statements)

References 5 publications

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“…HBV DNA integration were also identified in nuclei of hematopoietic stem cells from bone marrow of CHB patients using fluorescence in situ hybridization (FISH), as previously noted (see page 6) (Ma et al, 2011). HBV DNA integration into DNA of PBMC and lymphatic tissue were also occasionally found in other studies (Umeda et al, 2005;Wang et al, 2008).…”

Section: Hepadnavirus Integration Into Immune Cell and Lymphatic Organ Genomessupporting

confidence: 67%

“…Further investigations are required to determine the consequences of HBV and WHV integration considering immune cell physiological functions and a contribution to the pro-oncogenic processes culminating in lymphoproliferative disorders, such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia (Wang et al, 2008;Nath et al, 2010;Becker et al, 2012). Recognition of the integration kinetics, diversity of the host's sites involved, and the mechanisms mediating formation of virus-host junctions should be investigated.…”

Section: Hepadnavirus Integration Into Immune Cell and Lymphatic Organ Genomesmentioning

confidence: 99%

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Hepadnaviral Lymphotropism and Its Relevance to HBV Persistence and Pathogenesis

2021

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Since the discovery of hepatitis B virus (HBV) over five decades ago, there have been many independent studies showing presence of HBV genomes in cells of the immune system. However, the nature of HBV lymphotropism and its significance with respect to HBV biology, persistence and the pathogenesis of liver and extrahepatic disorders remains underappreciated. This is in contrast to studies of other viral pathogens in which the capability to infect immune cells is an area of active investigation. Indeed, in some viral infections, lymphotropism may be essential, and even a primary mechanism of viral persistence, and a major contributor to disease pathogenesis. Nevertheless, there are advances in understanding of HBV lymphotropism in recent years due to cumulative evidence showing that: (i) lymphoid cells are a reservoir of replicating HBV, (ii) are a site of HBV-host DNA integration and (iii) virus genomic diversification leading to pathogenic variants, and (iv) they play a role in HBV resistance to antiviral therapy and (v) likely contribute to reactivation of hepatitis B. Further support for HBV lymphotropic nature is provided by studies in a model infection with the closely related woodchuck hepatitis virus (WHV) naturally infecting susceptible marmots. This animal model faithfully reproduces many aspects of HBV biology, including its replication scheme, tissue tropism, and induction of both symptomatic and silent infections, immunological processes accompanying infection, and progressing liver disease culminating in hepatocellular carcinoma. The most robust evidence came from the ability of WHV to establish persistent infection of the immune system that may not engage the liver when small quantities of virus are experimentally administered or naturally transmitted into virus-naïve animals. Although the concept of HBV lymphotropism is not new, it remains controversial and not accepted by conventional HBV researchers. This review summarizes research advances on HBV and hepadnaviral lymphotropism including the role of immune cells infection in viral persistence and the pathogenesis of HBV-induced liver and extrahepatic diseases. Finally, we discuss the role of immune cells in HBV diagnosis and assessment of antiviral therapy efficacy.

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Section: Hepadnavirus Integration Into Immune Cell and Lymphatic Organ Genomessupporting

confidence: 67%

Section: Hepadnavirus Integration Into Immune Cell and Lymphatic Organ Genomesmentioning

confidence: 99%

Hepadnaviral Lymphotropism and Its Relevance to HBV Persistence and Pathogenesis

2021

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“…FISH was performed according to Wang . In our study, material from three sources was examined; CD34 + cells from the patients, CD34 + cells from healthy donors and HepG2.2.15 cells as the positive control (obtained from Medical University Chong Qing, China).…”

Section: Reverse Transcription Polymerase Chain Reaction (Rt‐pcr) Andmentioning

confidence: 99%

Infected hematopoietic stem cells and with integrated HBV DNA generate defective T cells in chronic HBV infection patients

Shi

Lan

Cao

et al. 2014

Journal of Viral Hepatitis

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A weak T-cell response plays a key role in the persistence of hepatitis B virus (HBV) infection. We aimed to confirm that T-cell defects in patients with chronic HBV infection are associated with HBV DNA infection of bone marrow (BM) hematopoietic stem cells (HSCs). Using reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH), we observed the transcription of HBsAg coding genes and confirmed the integration of HBV DNA in CD34+ BM HSCs from chronic HBV infection patients. T cells were generated by coculturing the HSCs with delta-like ligand 1-expressing OP9 (OP9-DL1) cells. The phenotypes of the T cells were then evaluated by flow cytometric (FACS) analysis on days 14 and 25. The results demonstrated that fewer CD3+TCRaβ+ CD3+CD4+ and CD4+CD8+ T cells were generated from the HSCs of the patients than from the healthy controls, (P < 0.01) but the frequency of CD3+D8+ T cells was not significantly different between the two group (P > 0.05). In contrast, CD4+CD25+ T cells were more in the patient group than in healthy controls (P < 0.01) on both days 14 and 25. There were fewer CD3+CD4+/CD3+CD8+ cells in the patient group than in the healthy control group on day 25 (P < 0.05). Less proliferation and lower levels of IL-2 and IFN- γ were also observed in the patient group compared with the control group (P < 0.05).These data suggest that HBV DNA infected and integrated into the BM HSCs from patients with chronic HBV infection and that these BM HSCs generated defective T cells.

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“…However, some CpCpC→CpCpT motif mutations may be caused by cytosine deamination of APOBEC3G in the antiviral process . (d) Small insertions and deletions caused by the sliding of the polymerase in homologous or random repeats . (e) The cleavage and religation activity of DNA strands by DNA topoisomerase I was recently shown to account for transcription‐associated mutagenesis.…”

Section: Introductionmentioning

confidence: 99%

Distribution and difference of APOBEC‐induced mutations in the TpCpW context of HBV DNA between HCC and non‐HCC

Ren

et al. 2019

Journal of Medical Virology

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Hepatitis B virus (HBV) DNA is vulnerable to editing by human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases. However, the distribution of APOBEC-induced mutations on HBV DNA is not well characterized.To this end, we obtained the HBV DNA sequence of HBV-infected individuals with and without hepatocellular carcinoma (HCC and non-HCC groups, respectively) from NCBI database and calculated the r apo values of APOBEC-induced TpCpW→TpKpW mutation prevalence in HBV DNA. The results showed that the APOBEC-induced mutations were mainly distributed in the minus strand of non-HCC-derived HBV DNA (r apo = 2.04), while the mutation on the plus-strand was weaker (r apo = 0.99). There were high APOBEC-induced mutation regions in the minus strand of HBV DNA 1 to 1000 nucleotides (nts) region and in the plus-strand of HBV DNA 1000 to 1500 nts region; the mutations in the 1 to 1000 nts region were mainly TpCpW→TpTpW mutation types (total T/G: 111/18) and a number of these were missense mutations (missense/ synonymous: 35/94 in P gene, 17/15 in S gene, and 5/10 in X gene). The difference between minus to plus-strand r apo of HCC-derived HBV DNA (1.96) was greater than that of the non-HCC group (1.05). The minus-strand r apo of HCC-derived HBV DNA regions 1000 to1500nts and 1500 to 2000 nts (r apo = 4.2 and 4.2) was also higher than that of the same regions of non-HCC-derived HBV DNA (r apo = 1.2 and 1.1). Finally, the ratio of minus to plus-strand r apo was used to distinguish HCC-derived HBV DNA from non-HCC-derived HBV DNA. This study unraveled the distribution characteristics of APOBEC-induced mutations on double strands of HBV DNA from HCC and non-HCC samples. Our findings would help understand the mechanism of APOBECs on HBV DNA and may provide important insights for the screening of HCC.

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Mutation analyses of integrated HBV genome in hepatitis B patients

Cited by 10 publications

References 5 publications

Hepadnaviral Lymphotropism and Its Relevance to HBV Persistence and Pathogenesis

Hepadnaviral Lymphotropism and Its Relevance to HBV Persistence and Pathogenesis

Infected hematopoietic stem cells and with integrated HBV DNA generate defective T cells in chronic HBV infection patients

Distribution and difference of APOBEC‐induced mutations in the TpCpW context of HBV DNA between HCC and non‐HCC

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