Seminar Abstract
Thursday, November 06, 2008 • 12:15 PM • Medium Conference Room, SFI
Avidan Neumann Bar-Ilan University, Ramat-Gan, Israel and SFI External Professor
A Paradigm Shift in Understanding Resistance Evolution Patterns with a Multi-Level Viral Dynamics Model Incorporating Intra-Cellular Replication
Background and goal: The current paradigm for modeling viral dynamics and the development of viral resistance, based on the HIV experience, considers the dynamics of the circulating virus and the cellular infection levels only (CI model). While this may be accurate enough approximation for HIV, a retrovirus RNA virus for which mutation occurs mainly at the RT step, it is known that for hepatitis C virus (HCV) all processes of resistance evolution – mutation, selection and amplification – can occur on a faster time-scale of RNA synthesis at the intra-cellular level. Here we explore, with a novel mathematical model (IC+CI model) that considers a multi-level dynamical process on both intra-cellular and cellular infection levels, the clinical implication of intra-cellular resistance evolution for direct anti-HCV drugs.
Methods: In the model, intra-cellular RNA (ICR) is used to form replication units (RU), which in turn synthesize more ICR that is partially packaged and secreted as virions. Direct anti-HCV drugs can have an anti-viral effect through blocking of RU formation, ICR synthesis and/or virion export. The development of resistance is modeled in the intra-cellular level by the evolution and dynamics of different strains of RU and ICR with different drug-sensitivity and different relative-fitness. Resistance evolution also impacts the cellular infection level as result of the exported virus from different strains.
Results: The IC+CI model gives rise to more viral kinetics scenarios than the CI model. In particular, a critical threshold of anti-viral effectiveness is predicted above which intra-cellular clearance of RU becomes the dominant viral dynamics process and viral decline is then governed by the rate of RU clearance (gamma). On the other, below that critical effectiveness threshold, as is probably the case for the standard IFN-a based therapy, viral decline is governed by the slower loss rate of infected cells (delta), similar to viral decline in the simpler CI model.
Furthermore, evolution of resistant virus is faster when it occurs at the intra-cellular level as compared to occurring only at the cellular infection level. The interplay between resistance evolution dynamics on the intra-cellular level with cell infection dynamics on the circulation level allows for more complex resistance evolution patterns than possible with resistance evolution on the cellular infection level only. In particular, we observe new patterns such as: a tri-phasic decline, a bi-phasic decline with a shoulder, continuous viral decline with fully resistance virus or a transient rebound with resistant virus followed by viral decline. Contrary to the current paradigm, these scenarios can, with realistic viral dynamic parameters, result in viral eradication even if a fully resistant virus has emerged and became dominant.
Conclusions: More rapid and more complex patterns of viral resistance evolution are predicted when considering HCV resistance evolution at the intra-cellular level together with cellular level viral dynamics. Some of the patterns predicted by the model were already observed in data publicly released for different direct anti-HCV drugs. The model allows for several predictions with important clinical implications.