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An Ancient Virus Lurking in Our Genes Could Play an Important Role in Some Addictions

MIKE MCRAE
28 SEP 2018

An unusual version of a retrovirus nestled between genes involved in brain chemistry is more common in individuals with a drug dependency than the rest of the population.

Researchers now have evidence that this pathogen could be responsible for a change in neurochemistry that puts some at a greater risk of developing an addiction, potentially making it the third significantly harmful human retrovirus ever discovered.

 

In a recent study led by researchers from the University of Oxford and the University of Athens, scientists showed how the genetic bones of a seemingly dormant virus influence nearby genes, one of which is involved in dopaminergic activity.

Our genome is a virtual graveyard of ancient microbial skeletons – coding for retroviruses that copied themselves into our DNA, typically losing their ability to reproduce their way out again.

"Most people think these ancient viruses are harmless," says epidemiologist Gkikas Magiorkinis from the University of Athens.

It's true - most of them seem to be harmless. They could make up as much as 8 percent of our own coding in one form or another.

Human Endogenous Retrovirus Type K (HML-2) – or HK2 for short – is a relatively recent example, at least as far as endogenous retroviruses go. We all carry its genes, and have done for the past quarter of a million years.

Unlike many other retroviruses lurking in our genetic code, HK2 might not be all that dead. Its code implies it's still functional, capable of creating viral particles that might make it infectious.

 

That's not to say it is 'alive', or that it's even dangerous. But this new discovery could change how we view it.

As ubiquitous as HK2 is, there are variants throughout our global population. One in particular found in about 5 to 10 percent of the population sits nestled inbetween two coding sequences for the gene responsible for a protein called RASGRF2.

The protein's role is linked with the release of neurotransmitters, particularly the chemical dopamine – an important messenger in the brain's reward pathway.

Having a different version of RASGRF2 has been linked with alcoholism in teens, and the gene has also been investigated in managing the buzz from alcohol in mouse brains.

So having a potentially functional retrovirus sitting inside the gene makes it an alluring candidate to examine for possible influences on addiction.

The researchers combed a UK database containing genetic information on individuals with Hepatitis C, as well as a similar Greek database on people with HIV.

They used this to determine a prevalence of the RASGRF2 version of HK2, one that showed a marked difference between individuals who had experienced intravenous drug use and those who hadn't.

 

Among the 184 individuals in the UK's sample, they were 3.6 times more likely to find the intruding virus among those infected with hepatitis-C as a result of chronic drug use.

Similarly, there was just over double the chance of finding HK2 inside RASGRF2 in chronic drug users among the 202 subjects analysed in the Greek HIV database.

To see if the intruding code could affect the gene's expression, they used CRISPR editing technology to slip the HK2 sequence into a typical RASGRF2 gene in a cell culture.

While the experiment couldn't go so far as to demonstrate complex changes in animal behaviour, they did show that artificially inserting the virus into a 'normal' RASGRF2 gene had profound effects on how it was interpreted and converted into a protein.

Of course, addiction is far more complicated than a simple gene change. Not all individuals in the study who had chronic drug dependencies had HK2 sitting inside this particular gene, and not all people with this viral variation had an addiction.

But the overlap suggests the virus could be a factor that tips some individuals over from occasional indulgence to something more serious.

 

Only two retroviruses are currently considered deadly to humans - HIV and Human T-Lymphotropic Virus.

While there is debate surrounding HK2's transmissibility, the discovery also poses interesting questions on just how dangerous our 'harmless' hidden retroviruses might be.

"Back in 2012, following a 20-year controversy regarding their pathogenic roles in humans, we sought to test the high-risk hypothesis that HERVs can be responsible for human disease," says Magiorkinis.

"For the first time, we are able to make a distinction between cause and effect in HERV pathogenicity."

This research was published in PNAS.