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New research from an international team led by Oxford University’s Department of Zoology and the National-Kapodistrian University of Athens, shows that an ancient retrovirus- HK2-is more frequently found in drug addicts and thus is significantly associated with addiction. Human genome is “littered” with remnants of ancient retrovirus infections that invaded the germline of human primate ancestors.
Only one of these may still be proliferating in modern humans named HERV-K HML-2 (HK2), and not all humans have the same HK2 viruses in their genomes. One specific uncommon HK2, which lies close to a gene involved in dopaminergic activity in the brain (RASGRF2), is more frequently found in drug addicts and thus is significantly associated with addiction.
The research teams have shown that HK2 can manipulate nearby genes. Their study provides strong evidence that uncommon HK2 integrations can be responsible for the unappreciated pathogenic burden of addictive behaviours. The team analysed samples of Hepatitis C Virus (HCV)-infected patients from the UK and HIV-infected patients from Greece who had become infected according to distinct, known routes of infection (injecting drugs), to determine the frequency of the HK2 integration in individuals. The particular HK2 insertion in the RASGRF2 gene is usually prevalent in 5-10% of the population.
This study shows that people with well-defined addictive behaviour i.e. Persons Who Inject Drugs (PWID) are 2 to 3 times more likely to have the integration of HK2 within RASGRF2 (a gene involved in regulating dopaminergic activity in the brain). It is thus a strong indication that HK2 within RASGRF2 predisposes these people in addictive behaviour.
Clear biological roles for a small number of human endogenous retroviruses. However, there has never before been strong evidence in support of a role in human biology of an endogenous retrovirus that is unfixed, in other words not shared by all individuals in the population. The study shows that rare variants of HK2 can affect a complex human trait.
Some people have shown overexpression of HK2 in cancer, but it has been difficult to distinguish cause from effect. 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. This shows that HERVs can be pathogenic. Most HERVs in the genome are shared by most human individuals. So if you pick two random people and check to see if they have the same HERVs in the same genomic location, it will be there. This is not true of some copies of HK2; there is variation, with certain individuals carrying extra copies in their genomes at distinct locations.
Since the discovery of HIV and (Human T-Lymphotropic Virus) HTLV, this is the third case in which a human retrovirus has been strongly linked with a harmful effect in humans. In this case, the harmful effect that researchers have identified is a complex behavioural condition. It could be said that this virus is ‘conditionally pathogenic’ as many individuals could carry it and not suffer negative consequences.
HIV spreads between individuals; differences in prevalence of HK2 are largely heritable, although it is possible that some HK2 viruses could still be infectious in the human populations. A very promising area of future research are the interactions between HK2 and other infectious human viruses. It is notable that the two cohorts of PWIDs that the researchers investigated are chronically infected with HIV and HCV respectively.
The researchers hope that by understanding the mechanistic-biochemical features of addictive behaviour better pharmacological targets can be developed for drug development. And as HK2 (the predictive factor) is a retrovirus it is possible that existing drugs could be used for research.