Mathematical Modeling as a Tool to Elucidate HCV Infection Kinetics and Treatment Response

Hepatitis C virus (HCV) treatment options have advanced significantly during the course of this thesis work, however, there are still approximately 170 million people chronically infected and our understanding of HCV infection dynamics and treatment response is still limited, restricting our ability to optimize the currently unaffordable treatment options, prevent re-infection of high risk individuals, and develop an effective vaccine. The underlying premise of this thesis is that by combining both experimental and modeling approaches we can achieve a more quantitative understanding of the viral lifecycle and develop mathematical tools to generate hypotheses and facilitate the investigations necessary to further our understanding of the system. While the modeling efforts in this thesis have utilized the HCV replicon system, the HCV cell culture (HCVcc) infection system, as well as kinetic data from chronically HCV-infected patients to yield quantitative estimates for drug efficacy and HCV infection parameters such as viral RNA stability/half-life, a focused goal of these combined approaches has been the development and refinement of the first data-driven multiscale model of HCV infection in vitro. The development and refinement of this model has been a process of discovery and is still not complete. Through the first iteration of our model we discovered that our understanding of chronic HCV infection was incomplete and obtained experimental evidence that supported the model prediction that non-productive HCV entry into infected cells plays a significant role in steady-state HCV dynamics. Subsequent analysis of the novel and multifunctional NS5a inhibitor, daclatasvir, revealed not only another important gap in our model regarding the specific infectivity of progeny virus produced, but also provided a plausible hypothesis regarding the new unexplained clinical phenomenon of patients who are positive for HCV RNA at the end of treatment, yet eventually achieve sustained virologic response (i.e. HCV cure) without additional treatment.