Retroviruses and amyotrophic lateral sclerosis

22 April 2011

lou gehrig columbiaAmyotrophic lateral sclerosis (ALS), also known as motor neuron disease or Lou Gehrig’s disease, is a fatal disorder of unknown etiology. The disease involves degeneration of motor neurons, leading to paralysis, respiratory failure, and death within five years. A viral etiology for ALS has been suggested but never proven. Retroviruses have been considered because they cause motor neuron disease in mice, and HIV-1 and HTLV-1 cause ALS-like symptoms in humans. Sera from some ALS patients have been shown to contain elevated levels of reverse transcriptase, an enzyme found in retrovirus particles. RNAs encoding this enzyme have now been found in the brains of ALS patients, and their origin appears to be the human endogenous retrovirus HERV-K.

Reverse transcriptase is a retroviral enzyme that makes a DNA copy of the viral RNA genome. It is present in the virion, a property that can be used to assay for reverse transcriptase activity. In one study of ALS patients, serum or cerebrospinal fluid is first centrifuged at low speeds to remove cells and debris. The cell-free extracts are then subjected to high speed centrifugation to pellet* viral particles. These are disrupted and an RNA template, a primer, and the precursors of DNA are added, and the mixture is incubated. A PCR reaction is then done; if any DNA has been made by reverse transcription, it will be amplified. In one study, 50% of ALS patients’ sera contained reverse transcriptase activity, at levels comparable to those found in AIDS patients. RT activity was detected in 7% of control sera.

What is the source of RT activity in sera from ALS patients? It does not appear to be from any known human exogenous retrovirus, including HIV-1, HIV-2, HTLV-1, HTLV-2, or HTLV-3. A recent study explored the possibility that the enzyme activity was due to the presence of the gammaretrovirus XMRV. However, the authors did not detect XMRV in DNA or RNA extracted from peripheral blood mononuclear cells of 20 ALS patients.

Human endogenous retroviruses are integrated into the human genome, but do not produce infectious virions and therefore are only transmitted through the germline. Although HERVs are highly mutated, some produce mRNA, viral proteins, and particles. At least 8% of the human genome consists of HERVs. One HERV, called HERV-K, may have integrated into the germline after the divergence of humans and chimpanzees.

The expression of HERV-K in ALS patients was examined in two ways: by PCR amplification of RNA extracted from brain tissues, using primers that amplify the pol gene (encoding RT), and by immunohistochemistry, using antibodies directed against the HERV-K reverse transcriptase protein. All samples used in the study were from patients who died of ALS (n=28), chronic systemic disease (n=10), accidental death (n=10) or Parkinson’s disease (n=12). HERV-K pol mRNA was detected in tissues from ALS patients and those who died of chronic systemic disease, but not from the accidental death or Parkinson’s patients. Levels of pol mRNA were highest in brains of ALS patients. Staining of brain sections with antibody to HERV-K pol revealed that the RT protein is produced only in neurons.

These observations raise a number of immediate questions. Is the RT activity detected in the serum of ALS patients from HERV-K? Why don’t all ALS patients have RT activity in their serum, and why is there such a wide range of HERV-K pol mRNA in the brain? Are the higher levels of HERV-K pol and RT observed in ALS patients a cause or a consequence of the disease? Answers to these questions will require more extensive epidemiological studies, and experiments to determine how HERV-K expression might lead to disease.

*pellet is jargon: the material at the bottom of a tube produced by centrifugation is a pellet, but scientists often use it as a verb, to indicate the separation of insoluble material by centrifugation.

[I used a photo of Lou Gehrig in a Columbia University uniform not only because I work at Columbia, but for several years I lived across the street from Gehrig’s birthplace, on 94th street and First Avenue in New York City. On a building across the street from my apartment was a plaque with the inscription ‘Lou Gehrig was born here’. I’d see it every day on my way to the lab. Years later, when I returned to look for the plaque, it had been stolen.]

McCormick AL, Brown RH Jr, Cudkowicz ME, Al-Chalabi A, & Garson JA (2008). Quantification of reverse transcriptase in ALS and elimination of a novel retroviral candidate. Neurology, 70 (4), 278-83 PMID: 18209202

Douville R, Liu J, Rothstein J, & Nath A (2011). Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Annals of neurology, 69 (1), 141-51 PMID: 21280084

  • Gob987

    McCormick et al did not use a validated assay.

  • http://profiles.google.com/zwilliams8377 Zachary Williams

    My first guess whenever I see endogenous retroviral activity associated with a disease is screwed up epigenetics. Genes getting expressed that are normally silenced.

  • Marie

    Herve Perron has found HERV-W protein envelope expressed in MS and schizophrenia. It is thought herpesviruses in adults comingle with HERV-W to create “a proinflammatory autoimmune cascade through interaction with Toll like receptor 4 on immune cells”. Apparently, embryonal cells with limited gene methylation are most susceptible to activation by viral infections. It may be the diseases occur as multi-step process as a result of exogenous viruses and other environmental factors that alter methylation and chromatin structures of cells. For more information of Herv’s in MS and schizophrenia see Perron’s article in the June 2010 issue of Discover magazine called “The Insanity Virus”. The field of epigenetics and HERV research is opening potential avenues for diagnosis and treatment complex disease like ALS, cancer, and neurological illnesses like MS and others.

  • Kati

    Hi Vincent, Dr Joe Brewer has tested 4 patients with ALS in his practice and 4 of them (100%) tested positive for XMRV. So the question is… why would an ERV, integrated for a long long time, would wake up- and why people keep rejecting Dr Mikovits, Alter, Lo, Ruscetti and Singh’s science?????

    Of interest also, a patient with ME/CFS tested negative for XMRV via blood, but tested positive for XMRV via a stomach biopsy. Of course this is self reporting, but interesting, none the less.

    Regards.

  • Gob987

    Exogenous retroviruses cause reactivation of endogenous ones.

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  • http://www.facebook.com/profile.php?id=1608101635 John Buettner

    Kati, has Dr. Brewer considered trying anti retroviral drugs on the 4 XMRV positive ALS patients? They’re facing a death sentence as it is, so isn’t it worth a shot?

  • Kati

    Treatment decision is between doctor and patients. It has not been made public what modality of treatment Dr Brewer is using at this point.

    What I know is whether you have a death sentence or a life sentence, both are very unpleasant and deserve compassionatec, appropriate and timely treatment.

  • http://www.facebook.com/profile.php?id=1608101635 John Buettner

    Because of the rapid progression of this disease I had hoped that the progress would be more public. I’m interested because a friend has ALS which makes my ME/CFS seem much less significant.

  • jbr123

    Hi,

    A couple of questions. Is the HERV-K RT activity cytoplasmic or only extracellular? If it is cytoplasmic, does the cellular HERV-K RT activity lead to an increase in dsDNA in the cell cytoplasm and would that be expected to activate an innate immune response (e.g. via TLR and RIG proteins)?

    Thanks.

  • Anonymous

    ME can be as severe as ALS and people have died from it. Obviously not in your case at this time.

  • Anonymous

    It is interesting that RT activity was detected in 7% of control sera.
    Compare this with Lombardi et al, who found XMRV in 3.7% of healthy controls and Lo/Alter et al. who found MLVrVs in a very similar 6.8% of controls.

  • Guest

    Did robert Gallo found these MLVs back in the 70s did he no they were there Vincent?

  • Gob987

    There were two other labs that found MLRVs in many different types of lymphoma and leukemia.

  • http://www.facebook.com/profile.php?id=1608101635 John Buettner

    No, not yet, but there were times that I wish I had.

    I’ve had this monkey on my back going on 26 years now and as you probably know, it goes in unpredictable cycles. I’ve been in a progressively deteriorating cycle now since October 2009 which has added peripheral neuropathy to the list of symptoms. This has greatly impacted my mobility, but still, it’s not the death sentence that comes with ALS.

  • http://www.facebook.com/profile.php?id=1608101635 John Buettner

    Discover magazine “The Insanity Virus”
    http://discovermagazine.com/2010/jun/03-the-insanity-virus

  • Gob987

    Maybe not for you, but it has been for others.

  • aidan walsh

    i wonder how many patients with als actually have 45% of the hiv virus envelope and also how many of them test positive to ciguatera (epitope) toxin and mycoplasma(s) and c. pneumonaie….unless the full truth is told to all of us we will never ever see a treatment protocol…stop with the lies and tell us all the full truth so we can all get on with our lives and the lawsuits…COVERUP. COVERUP.COVERUP. IS EXACTLY WHAT THIS IS AND WHEN ARE THEY GOING TO RECALL VACCINES AND COMPENSATE EVERYONE….SINCERELY AND ALWAYS THE TRUTH AIDAN WALSH SOUTHAMPTON, U.K. WE HAVE ALL HAD MORE THAN ENOUGH WITH THE PURE B.S.

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  • Dann Sarcoidosis

    My family tree is positive for neurosarcoidosis, mycosis fungoides, leiomyosarcoma, amelanotic melanoma, rhabdomyosarcoma. My brother’s high school friend has lung lymphoma and now ALS. Karen Duffy has neurosarcoidosis and her best friend has ALS. Mycosis fungoides is associated with HTLV-1 proviral DNA and borrelia. Morozov can find HTLV-1 particles in saliva of mycosis fungoides patients but not antibodies. So it’s either HTLV-1 provirus or borrelia.

  • http://twitter.com/janwly Janelle Wiley

    Very interesting and exciting development. Thanks, Proffessor.

  • John Buettner

    No, not yet anyway.

    And yes, it is a severe and disabling illness and after 26 years it has progressed to the point where I can no longer work.

    For the 1st time, I am getting an opportunity at a treatment. I just started Valtrex – 1,000 mg. 4 times a day for 6 months. At this point anything is worth a try.

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