NIH Director's Pioneer Award

Stanford University, Stanford CA

Investigators

Linked publications & trials

Abstract

The high error rate of the RNA-dependent RNA polymerases responsible for RNA viral[unreadable] genome replication presents an enormous challenge to successful drug therapy due to the high[unreadable] probability of mutations that can confer resistance to any antiviral pharmaceutical. Usually, the only[unreadable] solutions presented are multi-drug therapy, choosing a host-encoded target, or choosing the drug[unreadable] target such that resistant viruses are predicted to display only limited fitness; this latter option has[unreadable] not proved particularly successful due to the large amount of sequence space that can be explored[unreadable] by these highly mutable genomes.[unreadable] My laboratory has devoted considerable time to understanding the transmission genetics of[unreadable] positive-strand RNA viruses. Recently, we have consolidated this research to show that, for[unreadable] poliovirus, choices of drug target can be made so that drug-sensitive genomes dominantly inhibit[unreadable] the outgrowth of drug-resistant genomes. The ability of relatively unfit viruses to inhibit the growth[unreadable] of viruses with increased fitness derives from the intracellular amplification of positive-strand RNA[unreadable] viral genomes, their translation into large polyproteins and the higher-order oligomerization of[unreadable] several of their protein products. Here, I propose to use this understanding to identify ?dominant[unreadable] drug targets? for other positive-strand viruses such as rhinoviruses, coxsackieviruses, hepatitis C[unreadable] virus, Dengue virus and West Nile virus, informed by analogy with poliovirus and tested by direct[unreadable] genetic and biochemical investigation. This new paradigm will facilitate the development of[unreadable] therapeutics for which there is reduced danger of outgrowth of the inevitable drug-resistant[unreadable] genomes. My thesis is that theoretical and experimental understanding of the unusual genetics of[unreadable] intracellular viral growth can lead to the identification of ?Achilles? heels? for each targeted positivestand[unreadable] RNA virus, and possibly for other intracellular pathogens as well.