Life cycle synchronization is a viral drug resistance mechanism

• DOI: 10.1371/journal.pcbi.1005947
• Publication Date: 2018-02-15T18:27:41Z
• Authors: Iulia A. Neagu; Jason Olejarz; Mark Freeman; Daniel I.S. Rosen...; Martin A. Nowak; Alison L. Hill
• Keywords: Viral life cycle; Resistance mutation; Antiviral drug

Viral infections are one of the major causes death worldwide, with HIV infection alone resulting in over 1.2 million casualties per year. Antiviral drugs now being administered for a variety viral infections, including HIV, hepatitis B and C, influenza. These therapies target specific phase virus's life cycle, yet their ultimate success depends on factors, such as adherence to prescribed regimen emergence drug resistance. The epidemiology evolution resistance have been extensively characterized, it is generally assumed that arises from mutations alter susceptibility direct action drug. In this paper, we consider possibility virus population can evolve towards synchronizing its cycle pattern therapy. periodicity treatment could then allow strain whose length multiple dosing interval replicate only when concentration lowest. This process, referred "drug tolerance by synchronization", maximize overall fitness without having binding or complete drug's presence. We use mathematical models stochastic simulations show synchronization indeed be mechanism tolerance. effect more likely occur variability both dose timing low. More generally, find presence periodic levels, time-averaged calculations do not accurately predict levels needed eradicate infection, even if there no synchronization. derive an analytical expression sufficient explain drug-pattern-dependent survival strains any length. discuss implications these findings clinically relevant antiviral strategies.