COMPOSITIONS AND METHODS FOR TREATING RNA VIRUS INFECTION

COMPOSITIONS AND METHODS FOR TREATING RNA VIRUS INFECTION

Researchers at Stanford have developed a method of treating or preventing an infection from an RNA virus.

Viral pathogens are an ongoing threat to public health worldwide. Upon infection, RNA viruses must remodel host machinery to promote viral protein production while also suppressing host translation to evade host RNA surveillance and antiviral responses. Furthermore, RNA viral genomes are translated from a single open reading frame (ORF) into multidomain polyproteins that require host proteolytic processing and assembly. Dissecting their dependence on host biosynthetic pathways could lead to effective antiviral therapies.

Stage of Research

The inventors have integrated proteomic analyses of polysomes with functional genomics to define how entero- and flaviviruses remodel host translation machinery. The inventors demonstrate that viral infection by Polio, Dengue and Zika results in drastic remodeling of polysome composition. They further establish that these viruses use different strategies to evict a common set of translation initiation and RNA surveillance factors from polysomes, while recruiting host machineries specifically required for viral biogenesis. The inventors validate the importance of polysome remodeling and specialization through genetic and pharmacologic interventions. For example, both Zika and Dengue utilize collagen proline hydroxylation machinery to mediate co-translational modification of conserved prolines in the viral polyprotein, and inhibition of proline hydroxylation impairs viral polyprotein folding and lowers virus production. These findings delineate a modular nature of polysome specialization and establish a powerful strategy to identify targets for selective antiviral interventions.

Applications

Method to detect virus-specific changes in host proteins (e.g., non-canonical translation factors, chaperones and modifying enzymes) either recruited to or evicted from polysomes upon infection.
Strategy to identify targets for selective antiviral interventions.

Advantages

Method can capture distinct translation strategies of RNA viruses with different genome features, replication strategies and polyprotein architecture.
Viral-induced remodeling of translation initiation, chaperone recruitment, or other modifying enzymes can be genetically or pharmacologically targeted to destabilize viral polyproteins, disrupt polysome remodeling and lower overall viral biogenesis.

Stage of Development

Research – in vitro

Publications

Aviner R, Li KH, Frydman J, Andino R. Cotranslational prolyl hydroxylation is essential for flavivirus biogenesis. Nature. 2021. Doi: 10.1038/s41586-021-03851-2.

PCT publication no. WO2021/247953