Broad and rapid exploration of the mutational landscape by RNA viruses like influenza engenders high adaptability to environmental challenges. Understanding, predicting, and constraining RNA virus evolution requires a comprehensive picture of the molecular factors that define the accessible mutational landscape. Both the biophysical properties of viral protein variants and the ability of viruses as obligate parasites to hijack host protein folding mechanisms are expected to be important factors in this regard. Here, we test the hypothesis that the composition and activities of the host proteostasis network, composed of chaperones and quality control factors, is a critical mechanism that can both constrain and enable influenza evolution by both modulating overall selection pressure and by altering the fitness of specific viral protein variants. Chemical genetic and small molecule methods allow us to create diverse host cell proteostasis environments via either the stress-independent activation of heat shock factor 1 (HSF1) or the inhibition of HSP90 chaperones. Extensive propagation of influenza virus populations in these modified host proteostasis environments reveals that host proteostasis mechanisms influence both the strength of mutational selection on the influenza genome and the accessibility of specific mutational trajectories for diverse influenza proteins. Cumulatively, our data suggest that hijacking host proteostasis mechanisms to assist the folding and trafficking of viral protein variants with sub-optimal biophysical properties is a fundamental strategy used by influenza to enable more comprehensive exploration of the theoretically accessible mutational landscape.<br/>

Chemical biology strategies illuminating how the proteostasis network  modulates evolutionary excursions in sequence space by RNA viruses

253rd National Meeting (2017)

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