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

Abstract

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 hepatitismore » 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.« less

Authors:
ORCiD logo [1];  [2]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Memorial Univ. of Newfoundland, St. John's, NL (Canada). Molecular Virology and Hepatology Research Group
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1463503
Alternate Identifier(s):
OSTI ID: 1548049
Report Number(s):
LA-UR-18-22086
Journal ID: ISSN 0022-5193
Grant/Contract Number:  
AC52-06NA25396; R01-AI116868; R01-AI028433; R01-OD011095
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Theoretical Biology
Additional Journal Information:
Journal Volume: 455; Journal ID: ISSN 0022-5193
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 97 MATHEMATICS AND COMPUTING; Biological Science

Citation Formats

Goyal, Ashish, and Chauhan, Ranjit. The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection. United States: N. p., 2018. Web. doi:10.1016/j.jtbi.2018.06.020.
Goyal, Ashish, & Chauhan, Ranjit. The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection. United States. doi:10.1016/j.jtbi.2018.06.020.
Goyal, Ashish, and Chauhan, Ranjit. Sat . "The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection". United States. doi:10.1016/j.jtbi.2018.06.020. https://www.osti.gov/servlets/purl/1463503.
@article{osti_1463503,
title = {The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection},
author = {Goyal, Ashish and Chauhan, Ranjit},
abstractNote = {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.},
doi = {10.1016/j.jtbi.2018.06.020},
journal = {Journal of Theoretical Biology},
number = ,
volume = 455,
place = {United States},
year = {2018},
month = {6}
}

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