The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection

Goyal, Ashish; Chauhan, Ranjit

doi:10.1016/j.jtbi.2018.06.020

The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection

Journal Article · Sat Jun 30 00:00:00 EDT 2018 · Journal of Theoretical Biology

DOI:https://doi.org/10.1016/j.jtbi.2018.06.020· OSTI ID:1463503

^[1]; Chauhan, Ranjit ^[2]

Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Memorial Univ. of Newfoundland, St. John's, NL (Canada). Molecular Virology and Hepatology Research Group

Out of several phases of HBV infection, the least understood phase is occult hepatitis B virus infection. The paucity of data due to non-availability of biological tissues and the prerequisite of ultra-sensitive assays for the detection of occult hepatitis B virus infection prompted us to utilize mathematical modeling in determining mechanisms that lead to occult hepatitis B virus infection and characteristics of HBV infection during occult hepatitis B virus infection. In this paper, we proposed two mathematical models (M1 and M2), considering two different phenomenon for episomal maintenance and accumulation of covalently closed circular DNA (cccDNA) in infected hepatocytes: (i) M1 – recirculation of the relaxed circular DNA/double-stranded linear DNA from cytoplasm to the nucleus, and (ii) M2 – reinfection of infected hepatocytes with virions. We further incorporated the dynamics of integrated Hepatitis B virus DNA (iHBV) to investigate its role in the development of occult hepatitis B virus infection. The analysis showed that the main mechanism for the spread of infection during occult hepatitis B virus infection is cell-to-cell transmission and not cell-free virus transmission. A significant viral suppression (of at least 99% from its peak production values) was essential but not sufficient in the development of occult hepatitis B virus infection under M1; however under M2, the viral suppression was neither sufficient nor essential as the inhibition of the production of HBsAg without viral suppression can also explain the development of occult hepatitis B virus infection. Our analysis also revealed that occult hepatitis B virus infection seropositive cases are more likely to progress into liver cirrhosis compared to occult hepatitis B virus infection seronegative cases. The iHBV was found to be mostly silent (by either being absent or non-productive for HBsAg) during occult hepatitis B virus infection. The viral suppression is neither essential nor sufficient to explain the development of occult hepatitis B virus infection on its own. Not only the viral suppression but the inhibition -of the production and the export of HBsAg from cccDNA and iHBV also plays an important role in the development of occult hepatitis B virus infection. Finally, this is the first study, which incorporates the dynamics of iHBV and shows that HBV primarily spreads via cell-cell transmission during occult hepatitis B virus infection.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL)

Sponsoring Organization:: National Inst. of Health (NIH) (United States); USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1463503

Alternate ID(s):: OSTI ID: 1548049

Report Number(s):: LA-UR-18-22086

Journal Information:: Journal of Theoretical Biology, Journal Name: Journal of Theoretical Biology Vol. 455; ISSN 0022-5193

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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