STRANGE fevers and unusual infections are common among the people with HIV who come to Avindra Nath鈥檚 clinic for treatment. But when one young man showed up in 2005 struggling to move his arms and legs, Nath was baffled. Although the man had been diagnosed with HIV a few years earlier, his new symptoms matched those of amyotrophic lateral sclerosis (ALS), also known as motor neuron disease. In an attempt to get his HIV under control, Nath convinced him to start taking antiretroviral drugs. Much to everyone鈥檚 surprise, his ALS symptoms improved too.
ALS is caused by progressive deterioration and death of the nerve cells that control voluntary movement. What triggers this destruction is unclear, but recovery is rare. Puzzled, Nath, who ran an immunology clinic at Johns Hopkins University in Baltimore, began searching the medical literature. There he found other people with HIV and ALS whose ALS symptoms improved with antiretrovirals 鈥� drugs that stop viruses replicating. Could this neurological condition be triggered by a dormant virus hiding in our DNA, brought back to life by HIV?
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This question doesn鈥檛 only hover over ALS. Increasingly, we are waking up to the possibility that conditions including multiple sclerosis (MS), schizophrenia and even type 1 diabetes may in some cases be triggered by ancient viruses buried in our genomes. Under certain circumstances, they revive and start producing mutated versions of themselves, triggering the immune system to attack and destroy neighbouring tissues.
鈥淚t鈥檚 a wild new theory of disease,鈥� says Cedric Feschotte, a molecular biologist at Cornell University in New York. And already it is pointing the way to new treatments.
Most viruses are only temporary visitors. They make us sick, but soon we either get better or we die. A century ago, however, biologist Peyton Rous鈥檚 discovery of a cancer-causing virus provided the first clues that viruses can become resident in our DNA. The discovery began in 1910, when a woman knocked on his door at the Rockefeller Institute in New York, clutching her prized Plymouth Rock hen, which had a tumour called a sarcoma growing on its chest. Curious about its cause, Rous transplanted a small piece of the tumour into other chickens, and found that they developed a highly invasive cancer 鈥� even when the cancer cells and any accompanying bacteria were filtered out. The culprit was Rous sarcoma virus (RSV), a member of a previously unknown group of viruses called retroviruses, which insert a copy of their genome into the DNA of the cells they infect. This means they can reproduce without making infectious particles that could tip off the host鈥檚 immune system 鈥� something other viruses can鈥檛 do.
鈥淰iruses that have buried themselves in our DNA now occupy about 8 per cent of our genome鈥�
The discovery of retroviruses raised an intriguing possibility: if one were to infect a sperm or egg cell (see diagram), then viral DNA could be passed from parent to offspring through successive generations. Although scientists found no evidence that this happened with RSV, they soon identified several other retroviruses tucked away in the chicken genome. They named these endogenous retroviruses, because the viruses came from within an animal. By the mid-1980s, we had found them in humans, too.
The advent of genome sequencing in the 1990s revealed just how common these viruses are. Ever since they first evolved about 500 million years ago, countless retroviruses have buried themselves in the DNA of their hosts, to the extent that this ancient viral material now occupies about 8 per cent of the human genome. 鈥淵ou have to consider these viruses as a very, very old thing that happened to our ancestors millions of years ago,鈥� says Patrick K眉ry, a neuroscientist at Heinrich Heine University D眉sseldorf in Germany.
Over the millennia, most of these viral genes have become so riddled with mutations that they have become the genetic equivalent of fossils: inert and semi-degraded. There are a couple of exceptions. In humans, two families of retroviruses have been identified that, under certain circumstances, can reawaken and start producing small pieces of viral proteins that can activate the immune system. Not long after this discovery, signs started to emerge that these enemies within might be contributing to some relatively common human diseases.
Some of the first evidence came from people with MS, an autoimmune condition in which the body鈥檚 own immune cells start attacking the protective sheath that wraps around nerve cells, disrupting the messages they transmit. In 1989, Herv茅 Perron at the University of Lyon in France discovered an unknown retrovirus in brain tissue taken from people with the condition. Further experiments showed that the source of this virus was the human genome itself. Perron initially named the virus MS-associated retrovirus, but later sequencing of its genome revealed that it belonged to a new family of human endogenous retroviruses (HERVs) that became called HERV-W.
Perron鈥檚 work caught the eye of virologist Antonina Dolei at the University of Sassari in Sardinia, Italy. She began testing people with no known conditions for traces of Perron鈥檚 retrovirus and discovered an active form of the virus in 12.5 per cent of the general population. She also tested 39 people with MS and found it in every one of them. Brain tissue from people who had MS when they died also revealed the presence of retroviral protein.
鈥淚t was just incredible to see,鈥� says Dolei. 鈥淚f we can be aware of what鈥檚 actually going wrong in neurons, we can potentially change how MS is treated.鈥�
Dolei couldn鈥檛 initially determine whether Perron鈥檚 retrovirus was a cause of MS or a result of the disease process. But as she followed patients over time, she found that the amount of virus in the blood predicted the disease鈥檚 progression and severity. What鈥檚 more, the response to MS drugs and remission of symptoms correlated with reduced levels of retroviral proteins in the blood and the cerebrospinal fluid surrounding the brain and spinal cord. This suggested that HERV-W might somehow be playing a role.
Frankenstein鈥檚 molecules
By the time that young man walked into Nath鈥檚 HIV clinic in 2005, evidence was also mounting for the role of HERV-W in schizophrenia. , now at the Karolinska Institute in Stockholm, had identified traces of a retroviral protein called pol in the cerebrospinal fluid of about a third of people he examined who had been recently diagnosed with schizophrenia. Again, the source seemed to be the individuals鈥� own DNA.
As a retrovirologist, Nath had heard of Karlsson鈥檚 work, and, suspecting that his patient鈥檚 symptoms may have a similar cause, he approached Jeffrey Rothstein, an ALS expert who worked in a neighbouring lab. They started to examine brain tissue from 28 people who had had ALS when alive, and they detected RNA from a retrovirus called HERV-K in every single one. It was compelling evidence for the role of retroviruses in ALS, but still didn鈥檛 prove causation. Nath couldn鈥檛 rule out that dying nerve cells may have activated the virus.
It was similarly unclear how such activation might be contributing to nerve cell damage in schizophrenia or MS. The baton was picked up by K眉ry, who had been studying the cascade of events leading to the degeneration of nerve cells in MS. K眉ry realised that the evidence for HERV-W contributing to MS was circumstantial at best. 鈥淭he question in MS is always what comes first,鈥� says K眉ry. 鈥淭here has to be some trigger that sends the body towards an autoimmune response, but no one understands how this happens.鈥�
鈥淪tudies suggest that our cells may be less able to keep these viral elements suppressed during times of stress鈥�
K眉ry realised that he would have to look at how HERV-W interacts with neighbouring brain cells. Using brain tissue from deceased MS patients, K眉ry and his colleagues showed that a protein called ENV activates brain-based immune cells called microglia, which not only directly damage neurons, but also interfere with their repair. 鈥淣ow that we鈥檝e identified a protein, we can start to think about how to neutralise it with an antibody,鈥� says K眉ry, who published the results last year.
Although in some people with MS the body might be synthesising proteins from HERV-W and other endogenous retroviruses, Karlsson stresses that individuals aren鈥檛 producing a fully functional virus that can infect other people. Rather, it is something about the proteins produced and the body鈥檚 response to them that is the problem. In small studies of people with schizophrenia, scientists found slightly elevated levels of an inflammatory molecule called C-Reactive protein. This could indicate that, in some people, the immune system is responding to a virus. Karlsson still doesn鈥檛 know whether this is the result of endogenous retroviruses or how it might contribute to the condition.
Despite mounting evidence for the role of retroviruses in common illnesses, questions remain. For one thing, it is still unclear what proportion of MS, ALS and schizophrenia cases are related to the reactivation of these ancient viral stowaways. Their existence also doesn鈥檛 rule out other potential causes.
Another question is how we can carry copies of the viruses without feeling major ill effects. If HERV-W is thought to be buried in all our genomes, why does it only wake up and start causing problems in some people?
Our cells work hard to prevent these viral genes from being translated into proteins. The cell twists DNA into a complicated 3D snarl, and its protein-making machinery can only access genes on the surface of this tangle. As long as the hidden viruses remain buried in the middle, they are effectively silenced. And if that isn鈥檛 enough, the body has proteins whose main job is to suppress the production of any endogenous retroviral proteins. The slow accumulation of genetic mutations over time adds an additional layer of protection as they often render the viral proteins non-functional.
However, these fail-safes aren鈥檛 perfect, and studies suggest that our cells may be less able to keep these elements suppressed during times of stress. 鈥淲hen a cell is in crisis, it can make mistakes,鈥� says , a geneticist at Cold Spring Harbor Laboratory in New York. One such source of stress is infection with another virus.
Dolei notes that a disproportionate number of her MS patients report having experienced glandular fever (infectious mononucleosis) 鈥� caused by infection with the Epstein-Barr virus 鈥� as teenagers or young adults. Possibly, the infection triggers changes in DNA folding that leave some previously buried viruses exposed, prompting them to stagger to life like molecular versions of Frankenstein鈥檚 monster. In the case of people with HIV, their weakened immune systems may be less able to spot and destroy cells containing reactivated viruses.
Internal warfare
All humans have these fossil viruses in our DNA, and we all age and experience multiple infections, yet most of us will never develop MS, ALS or schizophrenia. K眉ry hypothesises that a combination of virus reactivation and a genetic predisposition is required to lead to illness. This may be bad news for individuals, but the reactivation of these clandestine viruses may also create the perfect Achilles鈥� heel in some of the conditions they cause.
As an HIV doctor in the late 1980s and early 1990s, Nath had a front-row seat to the lifesaving power of antiretroviral drugs. He prescribed them to all his patients 鈥� including the young man with ALS. That the drugs decreased the amount of HIV in the man鈥檚 blood and boosted his T-cell counts was no surprise to Nath. But the rapid improvement of ALS-like symptoms in people with HIV hinted that these drugs might be effective against other retroviruses: the resurrected fossils in our genomes. He is now recruiting people for a small pilot study to test whether giving a cocktail of three antiretroviral drugs is beneficial to people with ALS who don鈥檛 have HIV and who have high levels of HERV-K activity. A recent study suggests that this group may comprise a fifth of people with ALS.
Meanwhile, Hammell has used machine learning to analyse gene activity in brain cells from recently deceased ALS patients. Her analysis, published in October 2019 in Cell Reports, identified three subtypes of ALS, one of which was dominated by hidden viruses in the genome.
Possibly the biggest advance has come from a Swiss pharmaceutical company called GeNeuro, which Perron established in 2006 to develop new treatments for MS based on targeting retroviral proteins. GeNeuro is testing a drug called temelimab, which binds to the ENV protein from HERV-W and triggers its destruction. The results of a trial in 270 people with MS, presented at a scientific conference last September, suggests that the drug slows the shrinkage of brain tissue by 40 per cent. This is one of the most destructive consequences of the disease, and may be what leads to irreversible neurological and cognitive impairments. With existing MS therapies doing little to slow disease, Dolei says temelimab represents a huge advance.
The company has also begun testing temelimab in people with type 1 diabetes, another autoimmune condition, caused by the destruction of insulin-producing beta cells in the pancreas. The move comes after a 2017 study identified HERV-W activity in the pancreatic cells of about half of a group of people with type 1 diabetes. And the firm is working on antibodies to treat ALS and certain types of psychosis related to schizophrenia that have also been associated with retrovirus activation.
It is early days, but the development of such drugs could transform the war that has been raging between us and viruses since our earliest beginnings. 鈥淥ur cells have been fighting these things over evolutionary time scales 鈥� battles they have mostly won, in the sense that we are still here,鈥� says Hammell. With the drugs on our side we may win another important victory against the invisible enemies hidden in our genomes.
