For years, investigators have suspected that a retrovirus might be involved in the development of amyotrophic lateral sclerosis (ALS) since both murine and human retroviruses cause motor neuron disease-like syndromes.
In 2000, a team of British investigators led by WD Andrews reported an increased prevalence of a retroviral marker in the sera of British patients with ALS (J Med Virol 2000;61:527–532).
In February, the team reported similar findings in an analysis of US patients with ALS. Jeremy A. Garson, MD, PhD, one of the study authors from University College London, told Neurology Today that just under 50 percent of 30 US patients with ALS tested positive for the enzyme involved in the replication of retroviruses (Neurology 2005:64:454–458). In contrast, the retroviral marker – reverse transcriptase (RT) enzyme – was found in the blood of only 18 percent of unrelated controls and 13 percent of patients' spouses. The differences were significant (p-0.008). (See “Retroviral Marker: How it Works.”)
The retrovirus was also found in 43 percent of blood relatives of the ALS patients tested for the study, including seven children, one sibling, four parents, one aunt, and a cousin.
These results notwithstanding, the study authors noted that questions remain about the role the retrovirus play in causing the disease – that is, whether it is pathogenic, a co-factor for disease, or an incidental biological fluke.
NOT A NEW IDEA
In an editorial accompanying the Neurology study, Wim Robberecht of the University Hospital in Leuven, Belgium, and Burk Jubelt of SUNY Upstate Medical University in Syracuse, noted that although other studies on the involvement of viruses in ALS have not been very encouraging, there are reasons to take a closer look at retroviruses.
“An ALS like motor neuron disorder, potentially reversible, occurs in HIV-infected patients, and human T-lymphotropic virus type I causes an upper motor neuron disease: tropical spastic paraparesis,” they wrote. “Thus, retroviruses certainly deserve attention as a possible cause of motor neuron disease.”
There is also evidence that endogenous retroviruses – DNA sequences that have become part of the human over time – can cause motor neuron diseases that resemble ALS, said Benjamin Rix Brooks, MD, Professor of Neurology at the University of Wisconsin Hospital and Clinic in Madison, who was not involved in the study.
IS IT AN ENDOGENOUS RETROVIRUS?
The data from the new study do point to an endogenous retrovirus, said Dr. Garson. “The finding of a similarly increased prevalence in blood relatives of ALS patients raises the possibility that the observed (viral enzyme) activity might be due to an inherited endogenous retrovirus,” he and his colleagues wrote.
Endogenous retroviral sequences are normal components of all veterbrate genomes, Dr. Garson explained, and are thought to represent the remnants of ancient germ line infections by exogenous retroviruses.
If the retrovirus activity that the researchers saw were related to a viral infection that was exogenous – that is, it was transmitted through body fluids – you would expect to see a similar level in the patients' spouses because retroviruses can be transmitted via sexual intercourse, the investigators noted.
The high percentage of unaffected relatives of ALS patients who tested positive for RT, offers another clue to the disease. It suggests that the retrovirus may be necessary, but not sufficient to cause ALS, Dr. Garson said.
“In other words, the retroviral activity may not on its own be adequate to produce motor neuron degeneration but may require the presence of one or more additional co-factors,” he added.
“In a mouse model of age-related motor neuron disease which is associated with the activity of an endogenous retrovirus, the additional co-factor is known to be an infection with a second type of virus known as a togavirus” (J Virol 1989;63;4362–4369).
TIE IN WITH SPORADIC ALS
That fits in with some current thinking about the development of sporadic ALS, said Stanley H. Appel, MD, Chair of the Department of Neurology at the Neurologic Institute at the Methodist Hospital in Houston, TX. Dr. Appel was not involved in the study.
“Most of us feel that sporadic ALS is a multi-hit phenomenon,” Dr. Appel said. “An environmental factor may interact with one or more suspect genes. It's not one single event, per se.” Those other factors could be environmental toxins, Dr. Appel said.
In the end, researchers may learn more from healthy relatives of ALS patients who test positive for the retrovirus, Dr. Brooks said. “Just as Sherlock Holmes said, ‘What is significant about the dog is that it didn't bark,’” Dr. Brooks added. “We may learn something from the people who should have gotten ALS, but didn't.”
MORE QUESTIONS THAN ANSWERS
While the results are intriguing, they raise more questions than they answer. “We don't know if the retrovirus is actually triggering the disease,” said another study author Robert H. Brown, Jr., MD, DPhil, Professor of Neurology at the Harvard Medical School in Boston. “It also raises another question: If this is the activation of an intrinsic retrovirus, is this retrovirus important in sustaining the disease?”
Dr. Garson suggested that a retrovirus might lead to motor neuron degeneration and thus to ALS in these among other ways: through the accumulation of toxic retroviral envelope glycoproteins within glial cells or neurons; by excessive stimulation of excitatory amino acid receptors by retroviral proteins; and by retroviral-induced secretion of neurotoxic cytokines by glial cells or immune system cells.
The results are consistent with research being conducted by Dr. Brooks and his colleagues. “We had the same results which we presented as a poster a year ago in Milan,” he said. “This may tell us something about the disease, but it doesn't necessarily mean that the virus is causing ALS.”
Dr. Appel would like to see the authors tie up a few loose ends in future studies. “One of my concerns about this study is the set of controls,” Dr. Appel said. “They didn't look at the prevalence of retroviruses in cases of familial ALS, where we know that the defect is not due to the environment. It would be interesting to see if this is absent in familial cases or at the same level as in non-blood-related controls.”
It would also be interesting to see if there was evidence of retroviral activity in patients with other muscle diseases, Dr. Appel said. “It's not enough to use a normal control,” he added.
ALS experts said the finding could lead to better treatments for ALS if researchers can prove that retroviruses are actually involved in the development of the disease. “What is exciting is that we have animal models of viruses causing motor neuron diseases,” Dr. Brooks said. “This may mean something in terms of treatment.” If researchers can show that retroviruses play a role in the development of ALS, it could mean good news for patients. “The bottom line is that some retroviral infections have proven to be treatable and we'd like to find something in ALS that is also treatable,” Dr. Brown said.
A RETROVIRAL MARKER: HOW IT WORKS
The reverse transcriptase enzyme works like a factory assembly line, building the twisted zipper shape of DNA one piece, or base, at a time in a series of coordinated steps. It inserts its genetic code into the new DNA by using a strand of its own RNA as a template to which it attaches DNA's chemical building blocks, nucleoside compounds that it finds within the human cell.
After it grabs onto one of these building blocks, the enzyme clamps down around the growing DNA strand, maneuvering the nucleoside close to other compounds, causing a chemical reaction that adds a new piece to the growing strand of DNA. Drugs now used to fight HIV, such as AZT and ddC, work by locking into a site on the reverse transcriptase enzyme where the nucleoside compounds normally attach.
ARTICLE IN BRIEF
✓ Almost 50 percent of 30 US patients with ALS tested positive for the enzyme involved in the replication of retroviruses (Neurology 2005:64:454–458). In contrast, the retroviral marker – reverse transcriptase enzyme – was found in the blood of only 18 percent of unrelated controls and 13 percent of patients' spouses.