Pro-oncogenic, intra host viral quasispecies in Diffuse large B cell lymphoma patients with occult Hepatitis B Virus infection

Sinha, Mahua; Sundar, Keerthana; Premalata, C S; Asati, Vikas; Alka, Murali; Bajpai, Akhilesh Kumar; Davuluri, Sravanthi; Acharya, Kshitish K.; Lakshmaiah, K C; K, Govind Babu; Jacob, Linu Abraham; Nandan, Dharam; Velayutham, Dinesh; Datta, Sibnarayan; Jayshree, R. S.

doi:10.1038/s41598-019-51157-1

Cited by 18 publications

(14 citation statements)

References 40 publications

(65 reference statements)

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“…Next generation sequencing revealed the presence of genetic variants associated with increased HCC risk A1762T/G1764A in both the PBMC and DCS tumor [ 127 ]. Similarly, in a study of 40 HBV seronegative DLBCL patients, Sinha et al identified occult HBV infection within 27 (67.5%) cases [ 140 ]. Furthermore, they reported the detection of HCC-associated HBV genetic variants such as X/BCP/PC and surface mutations within plasma, B-cells, and tumor tissues.…”

Section: Unique Features Of Hbv That Impact Treatment and Oncogenementioning

confidence: 99%

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

2020

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Chronic Hepatitis B Virus (HBV) infection poses a significant global health burden. Although, effective treatment and vaccinations against HBV are available, challenges still exist, particularly in the development of curative therapies. The dynamic nature and unique features of HBV such as viral variants, integration of HBV DNA into host chromosomes, and extrahepatic reservoirs are considerations towards understanding the virus biology and developing improved anti-HBV treatments. In this review, we highlight the importance of these viral characteristics in the context of treatment and oncogenesis. Viral genotype and genetic variants can serve as important predictive factors for therapeutic response and outcomes in addition to oncogenic risk. HBV integration, particularly in coding genes, is implicated in the development of hepatocellular carcinoma. Furthermore, we will discuss emerging research that has identified various HBV nucleic acids and infection markers within extrahepatic sites (lymphoid cells). Intriguingly, the presence of hepatocellular carcinoma (HCC)-associated HBV variants and viral integration within the lymphoid cells may contribute towards the development of extrahepatic malignancies. Improved understanding of these HBV characteristics will enhance the development of a cure for chronic HBV infection.

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Section: Unique Features Of Hbv That Impact Treatment and Oncogenementioning

confidence: 99%

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

2020

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“…Although hepatitis B virus (HBV) is an essentially hepatotropic DNA virus, it also exhibits the capacity to infect peripheral blood mononuclear cells, including non-Hodgkin lymphoma (NHL) cells. 1,2 Besides being a risk factor for developing hepatocellular carcinoma, epidemiologic studies have suggested that chronic HBV infection can increase the risk of B-cell NHL, and it has been endorsed in a recent meta-analysis showing that HBV infection is significantly associated with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). 3 Patients with occult HBV infection (presence of HBV DNA in liver and/or serum, with undetectable hepatitis B surface antigen [HBsAg]) and resolved HBV infection (HBsAg − and anti-HBcore + [anti-HBc + ]) have been shown to contribute to the risk of developing NHL, although these situations are not considered in some studies because of the inadequacy of such information.…”

Section: Introductionmentioning

confidence: 99%

Worse outcome and distinct mutational pattern in follicular lymphoma with anti-HBc positivity

et al. 2022

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Epidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphomas (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 FL patients for HBV infection status, clinical features and gene mutational profile. Anti-HBc was detectable in sixteen patients (13.2%), although all had undetectable HBV DNA. Anti-HBc+ cases presented with older age at diagnosis than anti-HBc- cases (68.1 vs. 57.2 years, P=0.007) and higher β2-microglobulin (56.3% vs. 28.9%, P=0.04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV-hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year PFS (12.9% vs 58.3%; P<0.0001) and OS (22.0% vs. 86.2%, P<0.0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, two key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile.

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“…This study pointed out the importance of thorough analysis of immune cells from HBV-infected patients for the presence of virus and its integration. This study provides further invaluable insights to recognition of the relationship between HBV and immune system malignancies and suspected virusoncogenic potential (Engels et al, 2010;Li et al, 2018;Ren et al, 2018;Sinha et al, 2019).…”

Section: Hepadnavirus Integration Into Immune Cell and Lymphatic Organ Genomesmentioning

confidence: 90%

“…Furthermore, next generation sequencing of HBV-infected PBMC from CHB patients showed the presence of genetic variants associated with enhanced risk of HCC development (i.e., A1762T/G1764A) (Lau et al, 2020). In another study, OBI was identified in the majority (67.5%) of patients with diffuse large B cell lymphoma and HCCassociated HBV variants were identified in plasma, PBMC and lymphoid tumor tissue of these patients (Sinha et al, 2019). These data overall support the longstanding concept regarding the oncogenic role of HBV lymphotropism in the pathogenesis of immune cell malignancies.…”

Section: Hbv Integrationmentioning

confidence: 95%

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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Pro-oncogenic, intra host viral quasispecies in Diffuse large B cell lymphoma patients with occult Hepatitis B Virus infection

Cited by 18 publications

References 40 publications

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

Worse outcome and distinct mutational pattern in follicular lymphoma with anti-HBc positivity

Hepadnaviral Lymphotropism and Its Relevance to HBV Persistence and Pathogenesis

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