The human genome is “littered” with remnants of ancient retrovirus infections that invaded the germline of our 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 Oxford University and University of Athens research teams have shown that HK2 can manipulate nearby genes in research published in Proceedings of the National Academy of Sciences. Their study provides strong evidence that uncommon HK2 integrations can be responsible for the unappreciated pathogenic burden of addictive behaviors.

The team analyzed 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 behavior; ie, 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 behavior.

Professor Katzourakis, from the University of Oxford, who co-directed the study said: "We know of 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. Our study shows for the first time that rare variants of HK2 can affect a complex human trait. The replication of this finding in the distinct Athens and Glasgow cohorts is particularly important."

Dr. Magiorkinis, from the University of Athens, who led the study added: "Most people think these ancient viruses are harmless. From time to time, 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. Our proposal was supported by the Medical Research Council, and now we have strong proof that HERVs can be pathogenic. For the first time, we are able to make a distinction between cause and effect in HERV pathogenicity."

The integration of the virus predates the emergence of modern humans, as it has been found in Neanderthal and Denisovan genomes, and therefore it is not the behavior of PWIDs that determines the presence of the virus. Rather, it is likely that the virus is associated with addictive behavior. Not all PWIDs carry this virus so there will be many other genetic and behavioral factors involved, but this is an important predictive factor in addiction. Furthermore, the researchers’ experimental work supports a causal role in the expression of RASGRF2 and, hence, addiction.

By providing support for a strong genetic predisposition of addictive behavior, the Oxford research team advocates in support of medical-pharmacological interventions in support of addicts. Their study shows that new sequencing technologies and large genomic projects, such as the 100,000 genomes project, will deliver enhanced understanding of genetic features that were previously not well-understood.

Dr. Magiorkinis said: "Looking into this 'dark' part of the genome will unlock more genomic secrets."

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. Amazingly, it appears there are some rare variants where the integrated virus is "coding competent." In other words, it is an unbroken blueprint that could be used to make more viruses that could be active and cause problems to the human host.

The researchers hope that by understanding the mechanistic-biochemical features of addictive behavior, 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 as starting points for research into this area.