How Human Evolution Created an Unintended Vulnerability to HCV

A new study found that almost all humans have a less active form of interferon lambda 4, a fact that leaves them vulnerable to HCV.

John McLauchlan, PhD

John McLauchlan, PhD

As humans evolved, they developed a vulnerability to hepatitis C virus (HCV), but according to new research a small group of humans appears to have avoided the deficit.

That’s the central finding of new research that looked into the evolution of the interferon lambda 4 (IFNL4) in humans. Study co-authors John McLauchlan, PhD, and Connor Bamford, PhD, both of the University of Glasgow, told MD Magazine® IFNL4 doesn’t respond to HCV the way one would expect.

“Typically, you would expect that an interferon gene will act against any virus but in this case, IFNL4 appears to promote the development of chronic infection after an acute phase of infection,” said the investigators.

Thus, in the fight between the immune system and HCV, IFNL4 represents a vulnerability that benefits HCV to the detriment of humans.

However, it wasn’t always that way.

McLauchlan and Bamford found that chimpanzees have a different, more active version of IFNL4 that allows them to better fight off HCV. What’s more, the researchers also found that a very small group of humans—members of hunter-gatherer tribes in Central Africa, known as Pygmies—have a version of IFNL4 that is similar to the chimpanzee variant, making members of these tribes uniquely protected against HCV.

The pair said the findings suggest the change in IFNL4 occurred very early in human evolution.

“This allowed us to become more susceptible to HCV,” McLauchlan and Bamford said. “We don’t think that the evolution of the IFNL4 gene in humans as necessarily driven by exposure to HCV, it is maybe more likely the virus has simply exploited a gap in our immune defense system.”

Connor Bamford, PhD

Connor Bamford, PhD

It’s not clear why a small group of humans has the rare version of IFNL4.

“We cannot tell whether Pygmies and some Africans retain an ancestral version that has persisted at a low level since humans and chimpanzees diverged or whether they have 're-evolved' it,” McLauchlan and Bamford said. “We think further study of Pygmies and these rare African carriers would help figure out how their immune systems differ compared to non-carriers, which would be a fascinating study.”

Their hypothesis is that environmental factors, including exposure to viruses or bacteria, might account for the variant.

Either way, the new understanding unlocks a number of potential research pathways, though there’s no longer a need to look at IFNL4 as a pathway to cure HCV, since direct-acting antivirals (DAAs) are so effective.

“In the past, interferon-alpha was the mainstay of treatment but is increasingly no longer used because of DAAs,” they said. “So we would not consider IFNL4 as a way of treating those who are HCV-infected.”

However, McLauchlan and Bamford said the findings do give a window into how viruses like HCV can sneak past human defenses.

“In terms of where our research goes from here, we now have the tools to look at other viruses such as HIV or hepatitis B, that are also chronic blood-borne infections and ask questions about whether and how these viruses may also have exploited the gap created by the evolution of IFNL4 in humans,” they said.

They added that researchers should also look more closely at the evolution of IFNL4, its interaction with viruses, and whether or not any other species have the same weak, inactive form of the interferon.

The study, “A polymorphic residue that attenuates the antiviral potential of interferon lambda 4 in hominid lineages,” was published online in PLOS Pathogens.

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