Compartmental Hepatitis B Virus (HBV) Evolution, Replication and Infectivity in vivo and ex vivo
Abstract
Hepatitis B Virus (HBV) is classically considered a hepatotropic virus, however, the presence of different HBV genomic molecules in lymphoid cells and tissues support its lymphotropic nature. Our previous studies showed that HBV evolved in a compartment- and disease phase-specific fashion. However, the effect of nucleos/tide analogue (NA) therapy on HBV evolution and replication in different compartments (i.e., liver, plasma and peripheral blood mononuclear cell (PBMC)) is unknown, as well as the replicative competence and infectious capacity of PBMC-derived HBV.
We hypothesize that HBV replicating in lymphoid cells is infectious, and the HBV evolves in PBMC and/or plasma in chronic hepatitis B (CHB) patients under the influence of NA therapy or host immune pressure (i.e., fulminant hepatitis B).
The study on HBV replication and genetic evolution in PBMC, liver and plasma of CHB patients under NA therapy revealed the HBV evolution varied between three compartments both before and after treatment. NA had little effect on HBV cccDNA level and persistence of mRNA in PBMC. The study on HBV genetic features in CHB carriers with acute-on-chronic liver failure (ACLF) revealed the frequent immune escape mutations with clusters of surface gene variants possibly associated with development of fulminant hepatitis B. Mitogen stimulation in PBMC of CHB patients revealed presence of replicating HBV, which can be upregulated in PBMC and exhibited infectious capacity to HepaRG cells in vitro.
In summary, our data suggests potent NAs have little effect on HBV cccDNA in liver and PBMC, which highlights the need for continued suppressive antiviral therapy. The HBV evolution varied between different compartments in CHB patients under NA therapy. Distinct variants in HBV surface gene were found to be associated with HBV fulminant hepatitis. Moreover, HBV residing in lymphoid cells is increased after mitogen stimulation of PBMC and infectious to a hepatocyte cell line. The study furthers our understanding of HBV lymphotropism, role on viral persistence and the pathogenesis of chronic hepatitis B.
Description
Keywords
Bioinformatics, Biology--Molecular, Virology, Biophysics--Medical
Citation
Gao, S. (2017). Compartmental Hepatitis B Virus (HBV) Evolution, Replication and Infectivity in vivo and ex vivo (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25378