Intracellular Hepatitis C Virus Modeling Predicts Infection Dynamics and Viral Protein Mechanisms
Abstract
Hepatitis C virus (HCV) infection is a global health problem, with nearly 2 million new infections occurring every year and up to 85% of these infections 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 life cycle. Here, we present a detailed mathematical model that represents the full hepatitis C virus life cycle. 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 higher 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 protein 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 life cycle.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 01, 2018
- Source ID
- 10.1128/jvi.02098-17
Entities
People
- Alan S. Perelson
- Anushree Chatterjee
- Gitanjali Subramanya
- Katherine A. Marsh
- Susan L. Uprichard
- Thomas R Aunins
Organizations
- Los Alamos National Laboratory
- Loyola University Chicago
- National Institutes of Health
- University of Colorado
- University of Colorado Boulder
- University of Illinois Urbana–Champaign