Virus population intrahost evolution

How do populations of microorganisms interact with, evolve and adapt to the host environment?

Go to the profile of Raul Andino
Aug 29, 2017
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The paper in Nature Communications is here: http://go.nature.com/2goofK7

In the classic view of infection, a microorganism infects a host and replicates in certain tissues, where it may cause damage and disease, before spreading to a new host. This classic view is now broadening to include how populations of microorganisms interact with, and respond to, the host environment, yielding a deeper understanding of the complex within-host environment, and how pathogens evolve and adapt within these environments.

Recent work examining the evolution of pathogens within single hosts has revealed the details of antiviral resistance evolution in chronic HIV infection 1, and mutations in influenza that dodge memory immunity in human populations 2. The importance of within-host dynamics to the epidemiology of viral pathogens like HIV and influenza is made clear by these studies. However, understanding the details of within-host virus evolution remains a difficult problem. In our recent paper in Nature Communications(D.O.I 10.1038/s41467-017-00354-5), we explore the selective pressures that drive poliovirus evolution during acute infection in mice, finding that virus populations rapidly restructure in response to the unique selective environments within different tissues.

The life cycle and pathogenesis of a virus are intimately linked to the tissues it infects. In the case of poliovirus, infection is asymptomatic in 99% of infected individuals. The development of paralytic poliomyelitis occurs when the virus spreads from the gut to the central nervous system (CNS), where damage leads to paralysis. Our work began with the observation that a poliovirus variant with a reduced evolutionary rate is unable to spread effectively to the CNS and is therefore less pathogenic. This attenuation is relaxed in mice with a compromised immune system, suggesting that the ability to adapt is required to overcome immune barriers within the host. But what defines these barriers to infection? And how does a viral population evolve to overcome them?

To answer these questions, we characterized the host response and the evolution of viral populations in infected animals. Using RNA sequencing to look at the changes in gene expression in tissues from infected mice, we found that each tissue deploys a unique set of genes expressed in response to virus infection. Looking more closely at the genes that define these individual responses, we found that many of them were involved in antiviral defense. Given the differences in their response to infection, each tissue is likely to place its own unique selective pressure on the infecting virus population. How can a virus population overcome these diverse challenges?

The secret to may lie in the composition of the viral population itself. Due to the high mutation rates and large sizes associated with virus populations, they exist as a swarm of mutants known as a “quasispecies”. This remarkable diversity provides a reservoir of potential innovations that be selected as environments, and the associated selective pressures change. By sequencing viral populations isolated from individual organs in infected mice, we found that each organ shapes the makeup of the quasispecies residing there, but these organ-resident populations are consistent between individual mice. The poliovirus variant with a reduced evolutionary rate cannot access the necessary mutations to overcome these specific selective pressures, potentially explaining its inability to cause disease.

The results presented in our paper emphasize that within-host spread is an evolutionary process. It also identifies important links between immunity, evolution, and pathogenesis during acute infection. In the future, these concepts may help to explain why some viruses are more pathogenic than others, or how to engineer attenuated viruses for use as vaccines by altering their ability to evolve effectively.

 

1.         Feder, A. F. et al. A spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host. PLoS Pathog. 13, e1006358 (2017).

2.         Xue, K. S. et al. Parallel evolution of influenza across multiple spatiotemporal scales. Elife 6, (2017).

Go to the profile of Raul Andino

Raul Andino

Professor, UCSF

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