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Abstract Viruses persist in nature owing to their extreme genetic heterogeneity and large –population sizes, which enable them to evade host immune defenses, escape anti-viral drugs, and adapt to new hosts. The persistence of viruses is challenging to study because mutations affect multiple virus genes, interactions among genes in their impacts on virus growth are seldom known, and measures of viral fitness have yet to be standardized. To address these challenges, we employed a data-driven computational model of cell infection by a virus. The infection model accounted for the kinetics of viral gene expression, functional gene-gene interactions, genome replication, and allocation of host cellular resources to produce progeny of vesicular stomatitis virus (VSV), a prototype RNA virus. We used this model to computationally probe how interactions among genes carrying up to 11 deleterious mutations affect different measures of virus fitness: single-cycle growth yields and multi-cycle rates of infection spread. Individual mutations were implemented by perturbing biophysical parameters associated with individual gene functions of the wild-type model. Our analysis revealed synergistic epistasis among deleterious mutations in their effects on virus yield; so adverse effects of single deleterious mutations were amplified by interaction. For the same mutations, multi-cycle infection spread indicated weak or negligible epistasis, where single mutations act alone in their effects on infection spread. These results were robust to simulation under high and low host resource environments. Our work highlights how different types and magnitudes of epistasis can arise for genetically identical virus variants, depending on the fitness measure. More broadly, gene-gene interactions can differently affect how viruses grow and spread.
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Host proteostasis modulates influenza evolution
Influenza viruses, commonly called flu, can evade our immune system and develop resistance to treatments by changing frequently. Specifically, mutations in their genome cause influenza proteins to change in ways that can help the virus evade our defences. However, these mutations come at a cost and can prevent the viral proteins from forming functional and stable three-dimensional shapes – a process known as protein folding – thereby hampering the virus’ ability to replicate. In human cells, proteins called chaperones can help our other proteins fold properly. Influenza viruses do not have their own chaperones and, instead, hijack those of their host. Host chaperones are therefore crucial to the virus’ ability to replicate. However, until now, it was not known if host chaperones can influence how these viruses evolve. Here, Phillips et al. used mammalian cells to study how host chaperones affect an evolving influenza population. First, cells were engineered to either have normal chaperone levels, elevated chaperone levels, or inactive chaperones. Next, the H3N2 influenza strain was grown in these different conditions for nearly 200 generations and sequenced to determine how the virus evolved in each distinctive host chaperone environment. Phillips et al. discovered that host chaperones affect the rate at which mutations accumulate in the influenza population, and also the types of mutations in the influenza genome. For instance, when a chaperone called Hsp90 was inactivated, mutations became prevalent in the viral population more slowly than in cells with normal or elevated chaperone levels. Moreover, some specific mutations fared better in cells with high chaperone levels, whilst others worked better in cells with inactivated chaperones. These results suggest that influenza evolution is affected by host chaperone levels in complex and important ways. Moreover, whether chaperones will promote or hinder the effects of any single mutation is difficult to predict ahead of time. This discovery is significant, as the chaperones available to influenza can vary in different tissues, organisms and infectious conditions, and may therefore influence the virus' ability to change and evolve in a context-specific manner. The findings are likely to extend to other viruses such as HIV and Ebola, which also hijack host chaperones for the same purpose. More work is now needed to systematically quantify these effects so that we can better predict how specific chaperones will affect the ability of viruses to adapt, especially in pathologically relevant conditions like fever or viral host-switching. In the future, such insights could help shape the design of treatments to which viruses do not evolve resistance.
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- Award ID(s):
- 1652390
- PAR ID:
- 10048770
- Date Published:
- Journal Name:
- eLife
- Volume:
- 6
- ISSN:
- 2050-084X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.7554/eLife.28652
