Henry Huang

RNA viruses have high mutation rates and large population sizes that produce an astonishing diversity of variants that allow them to adapt rapidly to a particular lifecycle, conceivably to become optimal, such that the extant wildtype sequence is more fit than any variants derived from it.

Analyses of viral sequences show that significant portions of their proteins are extremely well conserved: frequently shared by all viruses in the same genus. The corresponding RNA sequences typically contain many synonymous changes, indicating that mutations do occur at these sites, but no amino acid changes became fixed, suggesting that no neutral nor beneficial nonsynonymous changes exist at these sites.

We use Sindbis virus as a model system to test if RNA viruses are indeed extremely well-adapted, and thus largely resistant to change. We examined the viral promoter that is used for the production of the subgenomic mRNA synthesis, using in vivo evolution and mutagenesis approaches, to show that across most of the promoter, the wildtype sequence is the most fit; i.e., the promoter is essentially optimal. Similar approaches will be used to test if much of the protein sequence of the viruses are similarly optimal.

The results to date suggest a novel and general approach for designing antiviral drugs, by targeting the conserved protein and RNA sequences of the viruses. It promises to provide broad-spectrum antiviral drugs that are effective against the virus and that have minimal impact on host processes, with very low probabilities of drug-resistance.

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