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This content will become publicly available on March 21, 2019

Title: Intracellular hepatitis C modeling predicts infection dynamics and viral protein mechanisms

Hepatitis C virus infection is a global health problem, with nearly 2 million new infections occurring every year and up to 85% of these becoming chronic infections that pose serious long-term health risks. To effectively reduce the prevalence of HCV infection and associated diseases, it is important to understand the intracellular dynamics of the viral lifecycle. Here, we present a detailed mathematical model that represents the full hepatitis C lifecycle. It is the first full HCV model to be fit to acute intracellular infection data and the first to explore the functions of distinct viral proteins, probing multiple hypotheses of cis- and trans-acting mechanisms to provide insights for drug targeting. Model parameters were derived from the literature, experiments, and fitting to experimental intracellular viral RNA, extracellular viral titer, and HCV core and NS3 protein kinetic data from viral inoculation to steady-state. Our model predicts faster rates for protein translation and polyprotein cleavage than previous replicon models and demonstrates that the processes of translation and synthesis of viral RNA have the most influence on the levels of the species we tracked in experiments. Overall, our experimental data and the resulting mathematical infection model reveal information about the regulation of core proteinmore » during infection, produce specific insights into the roles of the viral core, NS5A, and NS5B proteins, and demonstrate the sensitivities of viral proteins and RNA to distinct reactions within the lifecycle.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ; ORCiD logo [5] ;  [6]
  1. Univ. of Colorado, Boulder, CO (United States). Dept. of Chemical and Biological Engineering
  2. Univ. of Illinois, Chicago, IL (United States). Dept. of Microbiology and Immunology
  3. Loyola Univ. Medical Center, Maywood, IL (United States)
  4. Univ. of Illinois, Chicago, IL (United States). Dept. of Microbiology and Immunology; Loyola Univ. Medical Center, Maywood, IL (United States)
  5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  6. Univ. of Colorado, Boulder, CO (United States). Dept. of Chemical and Biological Engineering, and BioFrontiers Inst.
Publication Date:
Report Number(s):
LA-UR-17-30646
Journal ID: ISSN 0022-538X; 1098-5514 (Electronic)
Grant/Contract Number:
AC52-06NA25396; R01-AI078881; R01-OD011095; R01-AI028433; R01-AI116868; D17AP00024
Type:
Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Name: Journal of Virology; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH); Defense Advanced Research Projects Agency (DARPA)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science
OSTI Identifier:
1431078