Introduction to CFS/ME
Earlier in the year, scientists announced that they had discovered a retroviral link to
Microscopic image of XMRV (Xenotropic murine leukemia virus-related virus) Deutsch: Abbildung von XMRV (Xenotropic murine leukemia virus-related viru) Virionen (Photo credit: Wikipedia)
Myalgic Encephalomyelitis/Chronic Fatigue SyndromeChronic fatigue syndrome, or CFS, is a variably debilitating and complex disorder characterized by profound fatigue that is not improved by bed rest and persists or relapses for a minimum of six months which may also be worsened by physical or mental activity. Persons with CFS most often function at a substantially lower level of activity than they were capable of before the onset of illness. In addition to these key defining characteristics, patients report various nonspecific symptoms, including weakness, muscle pain, impaired memory and/or mental concentration, insomnia, and post-exertional fatigue lasting more than 24 hours. In some cases, CFS can persist for years. Moreover, since many illnesses have incapacitating fatigue as a symptom, care must be taken to exclude other known and often treatable conditions before a diagnosis of CFS is made.(1,2,3)Patients also often reported the onset of severe fatigue after a flu like illness(4,5,6,7,8) leading to the term post viral fatigue syndrome which also satisfies the criteria defining CFS.Thus it was realized that some form of viral infection may play a role in the onset of CFS in earlier years. (ME/CFS).
The XMRV Retrovirus
The retrovirus named XMRV, or ‘ Xenotropic murine leukemia virus-related virus‘ is a gammaretrovirus. It is an enveloped retrovirus that belongs to the virus family Retroviridae and its name refers to its similarity to murine leukemia viruses (“MuLVs”).Xenotropic MLVs are endogenous retroviruses of mice – the viral DNA is integrated into the mouse genome. Mice produce low levels of the virus (a few infectious viruses per millilitre of blood) but the virus cannot reinfect mouse tissues ,hence the name ‘xenotropic’, meaning a virus that can grow in species other than that of its origin (9)
Retroviruses are unique in that they carry a diploid RNA genome that is reverse transcribed in the cytosol of the cell, into DNA by the enzyme reverse transcriptase.The DNA is then integrated into the host genome by an integrase enzyme and thereafter is referred of as a provirus. The virus then replicates as part of the host cell DNA making the infection permanent.
XMRV was first identified in humans by Robert H. Silverman, Ph.D., professor in the Department of Cancer Biology at the Cleveland Clinic Lerner Research Institute,in prostate cancer tissue of men with a specific genetic defect in their antiviral defense pathway.This cancer associated defect resulted in a glutamine being substituted for an arginine at position 462 of the RNase L enzyme, which reduces its catalytic activity.This missense mutation in the RNase L enzyme is known as “R462Q”.The enzyme ribonuclease L (RNase L) is part of the cell’s natural defense against viruses which when activated degrades cellular and viral RNA to halt viral replication.(10,11,12)In 2002, the “hereditary prostate cancer 1” locus (HPC1) was mapped to the RNase L gene, implicating it in the development of prostate cancer (12) Silverman hypothesised that “the putative linkage of RNase L alterations to HPC might reflect enhanced susceptibility to a viral agent” leading to the discovery of XMRV(13).Regarding prostate cancer and RNase mutation links,further research has given conflicting results with some studies announcing that the presence of various polymorphisms of the RNase L gene do not raise the risk of contracting prostate cancer while others indicate the opposite. (14)
Other Gammaretroviruses
Gammaretroviruses have long been known to infect animals,first being identified as a cancer causing pathogen in rodents, but XMRV is the first gammaretrovirus to have infiltrated the human genome and is only one of five retroviruses known to have “species jumped” from simians (i.e., monkeys) to infect humans.The other four are HIV1, HIV2 ,HTLV1 and HTLV2(human T-Cell lymphotrophic virus 2). (15)
XMRV and CFS
The scientists from the Whittemore Peterson Institute (WPI), located at the University of Nevada,Reno, and their collaborators from the National Cancer Institute and the Cleaveland Clinic, published their groundbreaking findings in the journal Science, in a paper entitled “Detection of Infectious Retrovirus, XMRV, in the Blood Cells of CFS Patients”(16,17)In it, they linked XMRV to human Chronic Fatigue Syndrom (CFS).
Blood samples from 101 CFS patients and 216 healthy controls were analysed using PCR (polymerase chain reaction) and the results showed that 67% of the CFS samples contained XMRV nucleic acid, as compared to only 3.7% of the healthy controls. XMRV is believed to contribute to symptoms of CFS by increasing cytokine levels which may be caused by chronic XMRV infection in immune cells meaning they are always reacting to the XMRV infection.It may also possibly lower blood oxygen levels,(15,16) as MLV coat protein disrupts red blood cells in mice (18) so this may also be the case in humans. After the original Science paper was submitted, the scientists continued to refine their test for XMRV and found that 95 percent ME/CFS samples tested positive for XMRV antibodies in the plasma (17), which is quite an astonishing finding.
In the new study, active XMRV infections were found in 3.7 percent of the healthy controls tested. Roughly the same degree of infection in healthy people has been found in the prostate research. If this is representative of the United States as a whole, then as many as 10 million Americans may carry the retrovirus.It is estimated that more than a million Americans are seriously ill with the disease. (Not everyone infected with XMRV will necessarily get chronic fatigue syndrome — in the same way that not all of the 1.1 million Americans infected with H.I.V. will get AIDS.)(9)As with the hypothesized link between RNase L mutations and prostate cancer,the evidence of a link between XMRV and prostate cancer is currently inconclusive with various studies giving conflicting results.(14,19,20)
Viral proteins were identified in both B and T lymphocytes, and infectious virus could be cultured from these cells.Nucleotide sequence analysis of two XMRV genomes cloned from patient samples revealed that the virus is >99% identical to the virus identified in prostate cancers. Nevertheless, the two XMRV genomes are sufficiently different to suggest that the two CFS patients were independently infected.(16,21)
However this does not mean that XMRV is a definite cause of CFS/MS. The samples could have come from regions where XMRV infection is common, CFS patients could be more susceptible to XMRV infection if they are already infected with something else i.e. XMRV could be a passenger infection or some genetic defect may leave cells more susceptible to it.The reasons why some patients with XMRV exhibit CFS symptoms while others lead perfectly healthy lives would also need to be examined.Thus the need for the findings must be verified by more extensive analysis of CFS and healthy populations worldwide.It is also possible that XMRV may be able to induce transcription of an endogenous virus according to Brigette Huber,a professor of pathology at Tufts University’s Sackler School of Graduate Biomedical Sciences in Boston.She has been studying the presence of an ancient retrovirus,HERV-K18,which is dormant in most people but active in patients with CFS and multiple sclerosis.(29)Epstein Barr virus has already demonstarted that it can do this.(29,30)
History of CFS
One of the earliest references to chronic fatigue of unexplained origin in literature is from the 19th century,when a New York neurologist,George Beard,published a paper describing something he called Neurasthenia.However a psychiatrist Van Deusen also introduced the term in the American Journal of Insanity in the same year although he was largely overlooked.Neurasthenia was described as a condition of nervous exhaustion characterized by undue fatigue at the slightest physical or mental exertion and some medical historians believe CFS may be the same modern-day version of this disorder.(22,23)
CFS became famous in 1984 after an outbreak around Lake Tahoe, in Nevada. Several hundred patients developed flu-like symptoms such as fever, sore throat and headaches that led to neurological problems including severe memory loss and inability to understand conversation. Most of the patients were infected with many viruses at once, including cytomegalovirus, Epstein-Barr and human herpesvirus 6. Their doctors were stumped. The Centers for Disease Control and Prevention dismissed the epidemic saying that the Tahoe doctors “had worked themselves into a frenzy.” and that these were psychiatric problems, according to Hillary Johnson, the author of “Osler’s Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic.(24,25)
The name ‘chronic fatigue syndrome’ was coined in 1987, with the use of the word “syndrome” rather than “disease” suggesting a psychiatric rather than a physical origin and “functioned as kind of a social punishment,” Johnson said in an op-ed piece for The New York Times. Sufferers were branded malingerers by families, friends, journalists and insurance companies, and were denied medical care. (It’s no coincidence that suicide is among the three leading causes of death among sufferers.) Soon the malady came to be widely considered a personality disorder or something that sufferers brought upon themselves. A recent study financed by the C.D.C. suggested that childhood trauma or sexual abuse, combined with a genetic inability to handle stress, is a key risk factor for chronic fatigue syndrome.(24,25,26)
In 1991, Dr. Elaine DeFreitas, a virologist at the Wistar Institute in Philadelphia, found retroviral DNA in 80 percent of 30 chronic fatigue patients.Some of them also had rare forms of cancer. The C.D.C. tried to replicate her effort, but did not follow her exacting methods for finding the virus. In addition, the centers’ blood samples became contaminated, and some people at the agency said that administrators ended the research prematurely. Rather than admit any such failure, the C.D.C. publicly criticized Dr. DeFreitas’s findings which had the knock on effect of dettering other researchers in the field and leading the search for the cause to be largely abandoned for 20 years.The focus on the psychological origins of the disease also distracted from looking for a biological cause.In addition, investigations over a decade ago by the inspector general for the Department of Health and Human Services and what was then called the General Accounting Office in America, revealed that for years government scientists had channeled millions meant for CFS research into other projects.(24)
X-associated neuroimmune disease
Judy Mikovits,the retrovirus expert at the Whittemore Peterson Institute, who led the recent study linking XMRV and CFS has coined a new name for the condition:X-assocaited neuroimmune disease.(24)Since many CFS patients also have developed cancer,this does add some weight to the theory that XMRV may also be linked to various forms of cancer.Morever,Mikovitis has found XMRV virus in samples going back to 1984 and in nearly all the patients who developed cancer. (24,21)
Transmission of XMRV
Since XMRV is in the blood it can be transmitted by any bloodbourne route.Experiments in Mikovits’s lab proved that the retrovirus can be transmitted via blood by infecting healthy cells from volunteers with material from XMRV-positive CFS patients.(29)It will need further study to see if it can be transmitted in other ways e.g sexual,respiratory transmission.
Discussion
It is also possible that XMRV may have weakened the immune system first and ‘opened the door’ for other viruses which could explain why patients in past epidemics have been infected with a variety of viruses at once.Chronic stress may also weaken the immune system and it has been shown that even mild sub- clinical depression in older people can do this,with duration of the depression being more important than the severity of it in affecting immunity.(27,28) Thus a weakened immune system may either help the entry of XMRV or lead to the virus being able to compromise even more cells than before and thus exacerbate the condition even further.The further stress of being constantly exhausted etc would create a feedback cycle which serves to propagate the virus and worsen the condition.Since XMRV is a retrovirus it can lay dormant for periods of time (viral latency) before becoming activated by some trigger.The genetic mutations in the RNaseL enzyme which led to the discovery of XMRV in the first place would also mean that the viral RNA is not chopped up effectively in the cell.Latent infections can also transform cells and promote uncontrolled cell division which would essentially cause cancer.This uncontrolled cell division would be the result of the random insertion of the viral genome into the host genome which could activate oncogenes and/or lead to the up or down regulation of cell regulatory genes such as checkpoint control genes .
Concluding Remarks
This discovery will offer hope to the many people with CFS who have been stigmatised for years as a result of this disease.It also means that anti-retroviral drugs now in use for treating AIDS could also be tested for efficacy in CFS cases.
References:
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