A virus that long ago spliced itself into the human genome may play a role in amyotrophic lateral sclerosis (ALS), the deadly muscle degenerative disease that crippled baseball great Lou Gehrig and ultimately took his life. That’s the controversial conclusion of a new study, which finds elevated levels of human endogenous retrovirus K (HERV-K) in the brains of 11 people who died from the disease.

“This certainly is interesting and provocative work,” says Raymond Roos, a neurologist at the University of Chicago in Illinois who treats and studies ALS but who was not involved with the finding. Still, even the scientists behind the work caution that more research is needed to confirm the link. “I’m very careful to say HERV-K doesn’t cause the disease but may play a role in the pathophysiology,” says study leader Avindra Nath, a neuroimmunologist at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. “The darn thing is in the chromosomes to begin with. It’s going to be very hard to prove causation.”

It was another retrovirus, HIV, that led Nath to first suspect a connection between viruses and ALS. In 2006, he was helping a patient control his HIV infection with antiretroviral drugs when he noticed that the man’s ALS also improved. “That intrigued me, and I looked in the ALS literature and saw that people had reported they could see reverse transcriptase in the blood.” Reverse transcriptase, an enzyme that converts RNA to DNA, is a hallmark of retroviruses, which use it to insert copies of their genes into chromosomes of their hosts.

No study had ever convincingly found a retrovirus in ALS patients. But researchers had only looked for viruses that came from outside the body. About 8% of the human genome consists of “endogenous” retroviruses such as HERV-K, which presumably are remnants of ancient viruses. These retroviruses initially infected a human egg or sperm cell and entrenched themselves in chromosomes, allowing them to spread from one generation to the next. Mutations ultimately disabled the incorporated retroviral DNA.

In 2011, Nath and co-workers reported that they had found increased levels of expression for one HERV-K gene in autopsied brains of people who died from ALS. Their new study, published online today in Science Translational Medicine, builds on the earlier work with analyses of more brains and supporting evidence from test tube and mouse experiments.

In about 10% of people with ALS, someone else in the family has the disease, which suggests it originated from an inherited aberrant gene. Nath and colleagues focused instead on what is known as sporadic ALS: cases in which people have no familial history of the condition. Bolstering their 2011 study, the team found elevated levels of three different HERV-K genes in the autopsied ALS brains. The researchers did not isolate the virus itself, which Nath notes is logistically difficult because it would require analyzing “fresh” brains shortly after death.

The researchers further showed in test tube experiments that adding HERV-K genes to cultures of neurons led to a significant die-off of the cells. Using a technique known as electroporation to insert an HERV-K gene into the brains of embryonic mice, the researchers showed similar neuronal damage. The researchers then engineered mice to express that HERV-K gene in all their neurons. Again, the gene led to neuronal mayhem, and the animals had muscular problems similar to what’s seen in ALS patients.

Some retrovirologists caution that the evidence remains thin that this endogenous virus causes ALS. John Coffin, who studies HERV-K at Tufts University in Boston, notes that high expression levels of genes from this retrovirus have been found in many conditions, including breast cancer, multiple sclerosis, schizophrenia, and melanoma, but none have been conclusively shown to be caused by it. “There are a lot of papers like this one,” Coffin says. “Upregulation of this group of endogenous viruses is a very common finding.”

Coffin says “group” because there are about 90 different HERV-Ks, and that’s another concern he has about the Nath lab’s work: The study does not show that all ALS patients had the exact same version of the virus in their brains. “I’m perfectly willing to accept that there’s toxicity, but I’m never entirely sure what to make of these types of experiments,” Coffin says. He notes that in 1970s and 1980s, so many investigators wrongly asserted that exogenous human viruses—the ones that move between people or, commonly, humans and animals—caused tumors that they became known as “rumor viruses.” “There is a fair amount of rumor virology around endogenous retroviruses causing disease.”

Even Nath stresses that he wants other labs to confirm his team’s findings. “I’ve worked with HIV for many years, and I’m aware of the pitfalls, and that’s why we wanted to make sure we were very, very careful before we stuck our necks out,” Nath says. “It took us 10 years to produce this paper.”

Nath is now launching a clinical study that will evaluate the impact of treating ALS patients who have high levels of HERV-K genes expressed in blood with a combination of four antiretroviral drugs used to treat HIV infection. The phase I study will primarily assess whether treatment for 24 weeks can lower HERV-K gene expression to undetectable levels, but Nath will also monitor the disease’s progression. Whether the anti-HIV drugs will even have an impact on HERV-K is unclear. The drugs target the reverse transcriptase and protease enzymes, which both viruses depend on, but differences exist between the HERV-K and HIV versions.

Coffin, who warns that antiretrovirals have toxicities, says the clinical trial is folly. “The rationale for that is nonexistent,” he says. Nath counters that there are about 40 cases described in the literature of ALS patients taking antiretrovirals, but it’s difficult to make sense of these reports—about half of which claimed improvements. “No one has ever done a systematic study,” he says.

Then again, Nath allows that increased expression of HERV-K genes in ALS patients may simply be the result of something else that’s causing the actual damage. “The reasons for skepticisms are very valid,” Nath says. “We could be wrong as well.”