Authors: Connor Bamford (University of Glasgow Centre for Virus Research, UK)
Take a look behind the scenes of a recent Future Virology review, entitled: ‘Comparative host genomics: Has recent human evolution affected our immune defense against hepatitis C virus?’, as we ask the authors about the importance of the IFNL4 gene and the work that’s still to be done in the field.
What inspired you to write this piece?
We were inspired to write this article to summarize the exciting recent developments in our understanding of how the genetics of different species, such as humans and chimpanzees, impacts on the outcome of virus infections like hepatitis C virus (HCV). Despite excellent antivirals, HCV will likely remain a very significant global health burden because of its ability as one of the only positive-sense RNA viruses to cause life-long chronic liver infections in humans. We think that we can learn a great deal from understanding HCV–human immunity interactions.
How has hepatitis C virus shaped human evolution?
We don’t think that HCV has shaped human evolution per se but that human evolution in response to other pathogens has led to genetic changes that then go on to impact HCV infection outcome in both positive and negative ways. Although HCV causes disease it does so after a significant amount of time, so it is not considered to be a strong enough selective pressure to change host population genetics rapidly.
What have we learnt from this variation?
Comparing genome sequences between susceptible host species or individuals within a population allows you to identify critical molecules that regulate infection and disease. Work over the last decade has uncovered that one gene, IFNL4, is pretty special when it comes to HCV as although it is considered an antiviral protein, it is actually associated with an enhanced rate of chronic HCV infections. Intriguingly a lot of humans have lost their IFNL4 gene and are better able to defend themselves against HCV but almost half the human population carry the version of the gene associated with HCV chronicity.
How has divergence from chimpanzees affected our immunity against HCV?
Our work and others have shown that humans have evolved an IFNL4 with different antiviral activities that can affect how they defend themselves against HCV. Our recent research found that humans have evolved an IFNL4 with low antiviral activity compared with our closest living relatives the chimpanzees, and this reduced activity is associated with an enhanced susceptibility of humans to chronic HCV infection. This enhanced susceptibility may have been corrected for by further mutations in the human population such as complete of IFNL4. We don’t yet know what drove these changes in human IFNL4.
What work are you hoping to do/ what do you think needs to be done in this area?
We think that the most important thing to be done about HCV and IFNL4 is to really understand how IFNL4 works inside an animal during viral infection but now that chimpanzees cannot be experimented on for ethical reasons, alternative animal–pathogen models need to be explored for HCV-related viruses and this requires a lot of effort to develop as unfortunately mice and rats do not make IFNL4.
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