Hepatitis C virus (HCV) infections are a global health problem, with an estimated 70 million chronic infections worldwide, which can lead to hepatocellular carcinoma and cirrhosis of the liver. To effectively reduce the prevalence of HCV infection and associated diseases, it is important to understand the intracellular dynamics of the infection. To help achieve this goal, we have designed an intracellular model for the lifecycle of the virus within a human liver cell, which provides key functional insights into viral replication.
In Step 1 of the model, the cytoplasmic HCV RNA associates with available ribosomes in a second order reaction to form a translation complex (TC) at a rate kTC. This complex then synthesizes the viral polyprotein in a first order reaction with rate constant ktranslation. In Step 2, the viral structural proteins S, and the nonstructural proteins NS3/4A, NS5A, and NS5B are cleaved simultaneously to represent the rapid processing of the viral polyprotein that has been shown in prior literature. In Step 3, we assume that cytoplasmic RNA and NS5B associate to form an RNA/NS5B complex at rate kRp5B, and a free host factor (HF) associates with NS5A to form a HF/NS5A complex at rate kHFC, both in second order reactions according to the reactant concentrations. These two complexes are then imported into the VMS in a second order reaction at rate kRip to produce a Rip complex (RNA plus-stranded intermediate) that will make minus-strand RNA. In Step 4, inside the VMS, the minus-strand is synthesized—creating a double-strand molecule (dsRNA)—in a first order reaction with rate constant kinititation. Next, in Step 5, the dsRNA molecule associates with NS5B to form the Rids complex (RNA double-stranded intermediate), a second order reaction at rate kRids, which then synthesizes new plus-strand RNA in a first order reaction with rate constant kreplication. This minus-strand remains in the VMS to continue synthesizing plus-strand RNA. New plus-strand RNA in the VMS can be exported into the cytoplasm in a first order reaction at rate koutRp, or, in Step 6, be assembled into the virion particle and exported from the cell through association with cytoplasmic structural protein, a second order reaction at rate kassembly.
This model is presented in the paper “Intracellular hepatitis C modeling predicts infection dynamics and viral protein mechanisms.” (Aunins, et al., 2017, Submitted)