Coffin, CarlaPatel, Nishi Harishkumar2024-07-112024-07-112024-07-04Patel, N. H. (2024). Investigating the unique immunological and virological characteristics of hepatitis B in special populations (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.https://hdl.handle.net/1880/119136https://doi.org/10.11575/PRISM/46732The hepatitis B virus (HBV) causes acute and chronic hepatitis B (CHB) infection. Most immunocompetent adults develop self-limiting acute hepatitis B and serum HBV surface antigen (HBsAg) clearance due to robust innate and adaptive anti-viral immune responses. If acute hepatitis B does not resolve within six months, with persistence of HBsAg in serum, it is diagnosed as CHB infection. In both acute and CHB, HBV covalently closed circular (ccc) DNA and integrated viral genome in host chromosomes persist within the hepatocyte and increase the risk of occult hepatitis B infection (OBI). Rarely, an exacerbated host anti-viral immune response and a cytokine storm can lead to acute liver failure (ALF). CHB is associated with high levels of subviral particles (i.e., HBsAg), suppression of innate immunity, and peripheral tolerance marked by T cell exhaustion. A cure for CHB will reduce the liver disease burden and need for lifelong anti-viral therapy. A complete (sterilizing) cure requires eradication of the HBV cccDNA reservoir and integrated viral genomes but is difficult to achieve. Thus, a functional cure that enhances host anti-viral immune response and clearance of HBsAg is the goal of new therapeutic approaches. We prospectively recruited three unique patient populations to investigate viral and/or immune factors associated with varying immune control of HBV infection: (i.e., OBI and human immunodeficiency virus co-infection, CHB and metabolic-dysfunction associated steatotic liver disease, and HBV induced ALF).We assessed standard and novel viral biomarkers, viral variants by Sanger and deep sequencing, serum cytokines and/or peripheral HBV specific T cell response by enzyme-linked immunosorbent spot assay (ELISpot). Complementary studies were performed in a transgenic mouse model of HBV. We found unique HBV variants associated with host immune escape, risk of reactivation, liver fibrosis and hepatocellular carcinoma development, which varied between patient cohorts. Patients with greater hepatic steatosis and metabolic syndrome displayed heightened pro-inflammatory cytokines, HBV-specific T cell responses, and suppression of HBV replication. Increased serum angiogenic factors were associated with improved prognosis (i.e., reduced need for liver transplant) in individuals with ALF. In conclusion, unique HBV variants and dynamic host anti-viral immune response are associated with reduced viremia and positive clinical outcomes in individuals with hepatitis B infection.enUniversity 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.Hepatitis B virusOccult hepatitis B and human immunodeficiency virus co-infectionChronic hepatitis BMetabolic-dysfunction associated steatotic liver diseaseAcute hepatitis BAcute liver failureVirologyMicrobiologyImmunologyBiology--Moleculardoctoral thesis