Persistent Hepatitis B Virus in Hepatic and Extrahepatic Reservoirs in Hepatitis B Virus Related Oncogenesis

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dc.contributor.advisorCoffin, Carla S.
dc.contributor.authorLau, Keith Chi Kei
dc.contributor.committeememberBurak, Kelly Warren
dc.contributor.committeememberMahoney, Douglas J.
dc.contributor.committeemembervan Marle, Guido
dc.date2020-11
dc.date.accessioned2020-05-14T17:14:10Z
dc.date.available2020-05-14T17:14:10Z
dc.date.issued2020-05-04
dc.description.abstractChronic infection by Hepatitis B virus (HBV) may result in hepatocellular carcinoma (HCC). Numerous viral factors are associated with oncogenesis and development of HCC, including integration, genetic variations in the X/basal core promoter/precore (X/BCP/PC) region, and occult infection. Although primarily hepatotropic, HBV is frequently found in circulating peripheral blood mononuclear cells (PBMCs) of the lymphoid system. Few studies have characterized this extrahepatic reservoir particularly in HBV-related HCC individuals. In this thesis, we hypothesized that pro-oncogenic HBV is present in both liver and extrahepatic reservoirs in chronic HBV (CHB) carriers with and without malignant disease. A highly sensitive molecular tool for accurate detection of low-level HBV and determination of genotype is described in this thesis. Subsequently, this technique was applied to plasma and PBMCs from post-liver transplant CHB carriers in combination with next generation sequencing to identify HCC-associated viral genotypes and genetic variants. The lymphoid reservoir in 32 CHB carriers with HCC and a representative patient with an extrahepatic lymphoid malignancy (i.e., dendritic cell sarcoma [DCS]), was evaluated for pro-oncogenic HBV. Interestingly, integrated virus was identified in genes implicated in cancer development in liver, PBMCs and DCS tumor. HCC-associated X/BCP/PC variants and genotypes were also present within lymphoid cells. Functional characterization of the most commonly detected variants (Guanine-1896-Adenine and Adenine-1762-Thymine/Guanine-1764-Adenine) were evaluated in vitro. Compared to wild-type, these mutants showed reduced viral HBeAg, modulated cytokine/chemokine expression, decreased APOBEC3G protein expression. The A1762T/G1764A mutant had more robust HBV replication than the G1896A variant. Overall, the findings in this thesis contributes to the literature on the epidemiological association of occult HBV, specific HBV SNPs, and integrated virus in hepatic and extrahepatic reservoirs. Persistent carcinogenic HBV poses continual risks of HCC recurrence and viral reactivation thus advocating for long-term HBV prophylaxis use post-transplant. Pro-oncogenic HBV within lymphoid cells may contribute towards oncogenesis of extrahepatic malignancies such as DCS. HCC-associated variants show functional differences in viral replicative fitness and host immune responses. Taken together, this thesis is significant for advancing the currently limited understanding of HBV molecular virology and pathogenesis of HBV-related carcinogenesis within the hepatic and extrahepatic reservoirs.en_US
dc.identifier.citationLau, K. C. K. (2020). Persistent Hepatitis B Virus in Hepatic and Extrahepatic Reservoirs in Hepatitis B Virus Related Oncogenesis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37827
dc.identifier.urihttp://hdl.handle.net/1880/112040
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectHepatitis B Virusen_US
dc.subjectHBV genetic variantsen_US
dc.subjectHBV-related HCCen_US
dc.subjectHepatocellular carcinomaen_US
dc.subjectChronic hepatic Ben_US
dc.subjectViral reservoirsen_US
dc.subjectExtrahepatic malignanciesen_US
dc.subject.classificationVirologyen_US
dc.titlePersistent Hepatitis B Virus in Hepatic and Extrahepatic Reservoirs in Hepatitis B Virus Related Oncogenesisen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Microbiology & Infectious Diseasesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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