Synchronization of Viral Lifecycle Length to Antiviral Drug Dosage Schedules and the Emergence of "Cryptic Resistance''

Abstract

Viral infections, such as HIV, are often treated with orally administered antiviral medications that are dosed at particular intervals, leading to periodic drug levels and hence periodic inhibition of viral replication. These drugs generally bind to viral proteins and inhibit particular steps in the viral lifecycle, and resistance often evolves due to point mutations in the virus that prevent the drug from binding its target. However, it has been proposed (Wahl \& Nowak, Proc Roy Soc B, 2000) that a completely different ``cryptic'' mechanism for resistance could exist: the virus population may evolve towards synchronizing its lifecycle with the pattern of drug treatment. If the lifecycle of the virus is a multiple of the dosing interval, it is possible that over time the bulk of the virus population will replicate during trough concentrations of the drug. In this thesis, we use stochastic mathematical models of viral dynamics to demonstrate that cryptic resistance could plausibly provide a powerful fitness advantage to a wide variety of viral strains whose expected lifecycle times are slightly less than the expected time between doses of an antiviral drug, allowing them to survive drug regimes that would otherwise drive infected cell populations to extinction. This in turn suggests that continuously-administered antiviral drug treatments may be significantly more effective than periodically-administered treatments in combatting viral infections.