Xenotropic MuLV-related virus
Encyclopedia
Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus
that was first described in 2006. Initial reports linked the virus to prostate cancer
, and later to chronic fatigue syndrome
(CFS), but these were followed by a large number of studies in which no association was found. It has not been established that XMRV can infect humans, nor has it been demonstrated that XMRV is associated with or causes human disease. Numerous researchers have suggested that XMRV detection may result from contamination of clinical specimens and laboratory reagents with mouse
retrovirus
es or related nucleic acid
s. Nevertheless, public health officials have voiced concerns about the donated blood
supply, citing the potential dangers should XMRV prove to be an infectious human pathogen
.
. It has a single-stranded RNA
genome
that replicates through a DNA
intermediate. Its name refers to its close relationship with the murine leukemia virus
es (“MuLVs”). The genome, approximately 8100 nucleotides in length, is 95% identical with several endogenous retrovirus
es of mice, and is 93-94% identical with several exogenous
mouse viruses.
Several XMRV genomic sequences have been published to date. These sequences are almost identical, an unusual finding as retroviruses replicate their genomes with relatively low fidelity, leading to divergent viral sequences in a single host organism. The results of phylogenetic analyses of XMRV and related murine retroviruses led a group of researchers to conclude that XMRV "might not be a genuine human pathogen".
at the University of California, San Francisco
, and Robert Silverman and Eric Klein of the Cleveland Clinic
. Silverman had previously cloned
and investigated the enzyme ribonuclease L
(RNase L), part of the cell’s natural defense against viruses. When activated, RNase L degrades cellular and viral RNA
to halt viral replication. In 2002, the “hereditary prostate cancer 1” locus (HPC1) was mapped to the RNase L gene, implicating it in the development of prostate cancer. The cancer-associated “R462Q” mutation results in a glutamine
instead of an arginine
at position 462 of the RNase L enzyme, reducing its catalytic activity. A man with two copies of this mutation has twice the risk of prostate cancer; one copy raises the risk by 50%.
Klein and Silverman hypothesized that “the putative linkage of RNase L alterations to HPC might reflect enhanced susceptibility to a viral agent”, leading to the discovery of XMRV.
containing samples of genetic material from about 950 viruses. The screen indicated the presence of a gammaretrovirus-like sequence in seven of eleven tumours homozygous for the R462Q mutation, but only in one of five tumours without the mutation. After isolation and cloning of the virus, an expanded screen found it present in 40% of tumours homozygous for R462Q and in only 1.5% of those not. A 2009 study reported evidence of XMRV infection in 23% of subjects independent of the RNase L gene variation, and detection of XMRV was again reported in a 2010 article.
However, numerous studies have failed to find evidence of XMRV in prostate cancer. Researchers in Germany found no XMRV-specific sequences in the DNA or RNA of samples from prostate cancer patients, and no XMRV-specific antibodies were detected in blood serum
samples. Another German study found no XMRV association with non-familial (sporadic) prostate cancer, and no XMRV link was found in Irish prostate cancer patients with the R462Q mutation. Similar results were reported in The Netherlands, Japan
, and Mexico
. Geographical differences were initially suspected as the culprit in these discrepancies, because the positive results were obtained in the United States. However, U.S. studies have also found no evidence of XMRV. Researchers at the National Cancer Institute
, Johns Hopkins and the Mayo Clinic tested over 1,000 samples from prostate cancer patients but found no evidence of the virus.
A causal role of XMRV in cancer has not been established, and XMRV does not appear to be capable of transforming cells
directly. In prostate cancer, XMRV protein has been found in tumour-associated but nonmalignant stromal cell
s, but in one study is was not found in the actual prostate cancer cells, raising the possibility that the virus may indirectly support tumorigenesis. However, in another study, XMRV proteins and nucleic acids were found in malignant cells.
(CFS) but in only 4% of healthy controls. The authors, Lombardi et al., reported that patient-derived XMRV could infect cells in vitro and stated that "These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS". The reported association of XMRV and CFS, published in Science, generated worldwide media coverage and subsequent conflicting study results. Independent laboratories from around the world have not detected XMRV in CFS patient groups or control populations, using blood samples or cerebrospinal fluid. Various PCR assays and antibody-based detection methods were used in these investigations. Some of the authors of the original CFS report suggested that the widespread failure to replicate their results was attributable to different PCR conditions or to different criteria used to classify patients. However, several negative studies have been conducted with the same PCR primers used in the first investigation. Another study using the original reaction conditions did not detect XMRV in UK patients who "not only had CFS, but had considerable disability". Another study found no XMRV, but did report detection of murine leukemia virus
related sequences in the blood of CFS patients. Two reviews have argued that reconciliation of these differences is necessary. The editor-in-chief of the journal Science in June 2011 published an expression of concern, stating that "the validity of the study by Lombardi et al. is now seriously in question". In September 2011, the original authors published a "Partial Retraction" of their 2009 findings, in which they acknowledged that "some of the CFS peripheral blood mononuclear cell (PBMC) DNA preparations are contaminated with XMRV plasmid DNA."
An international workshop was convened in September 2010 to aid in resolving the discrepancies. At the meeting, it was announced that Ian Lipkin
would oversee a multi-centre trial that would culminate in blinded testing of 150 CFS patients and 150 healthy but comparable donors by laboratories at the Whittemore Peterson Institute, the NIH and the CDC. The results of this multi-centre trial are expected to be available at the end of 2011.
, fibromyalgia
, multiple sclerosis
, amyotrophic lateral sclerosis
, and Parkinson's disease
. However, there is currently no evidence to support these hypotheses. No XMRV was found in 230 autistic children or in 204 controls, nor was XMRV detected in fibromyalgia or MS patients or in children with idiopathic diseases. In one study, XMRV was detected in a small percentage of patients with weakened immune systems, but other studies found no evidence of XMRV in immunosuppression. Out of more than 500 HIV-1-positive people, none was positive for XMRV, nor was XMRV found in systemic lupus erythematosis patients.
, for example as the result of contamination with nucleic acids from mice or mouse viruses. Most proposed retrovirus-disease associations have been prompted by accidental detection of contaminants, and initially promising results were later disproven or failed replication. Virologist Robin Weiss suggested in 2010 that XMRV is likely to be one of these "rumour viruses". The suspicion of contamination grew with an increasing number of negative studies as well as investigations demonstrating contamination.
The results of several studies support the contamination hypothesis. Scientists reported that they found ample sources of contamination in laboratory reagents, tissue samples and blood. Samples that were positive for XMRV were also positive for mouse DNA contaminants. Another article reported on the striking identity of XMRV genomic sequences and their similarity to xenotropic MLVs in several human cell lines. The authors conclude that XMRV contaminated 22Rv1 cell cultures, likely during passage in athymic mice
. (Production of laboratory cell lines may involve passaging of tumours in mice.) Identical XMRV integration sites were also found, a phenomenon never before reported for a retrovirus and strongly suggestive of contamination. It has been recommended that studies of XMRV should include more diverse and stringent PCR testing and phylogenetic analysis
to detect occurrence of mouse DNA contamination from laboratory sources.
Responding to indications of contamination, the group that reported an association of XMRV with CFS stated that its evidence was not restricted to nucleic acids, but also included antibody-based detection. Their study used murine leukaemia virus antibodies and antigens, not XMRV-specific reagents. Multiple studies have failed to detect XMRV by PCR or antibody-based methods. In one study, several samples that were PCR-negative contained antibodies that interacted with XMRV. However, the authors found that these antibodies were non-specific and also interacted with other viruses. Mayo Clinic researchers also reported on non-specific anti-XMRV antibodies. In another study, only low reactivity with XMRV antigens was found, with no differences between cases and controls. The authors noted that establishing a cutoff for seropositivity was impossible, as no positive sera
are available. A study that included samples from the original XMRV-CFS report found no XMRV in patients or controls by PCR, antibody-based methods or viral culture. The authors discovered that some PCR reagents were contaminated with low levels of mouse nucleic acid but pointed out that this could not explain the high XMRV positive rates reported initially.
found no XMRV in the semen of HIV-positive men. Both cell-associated and cell-free transmission have been reported in vitro. XMRV is closely related to several known xenotropic mouse viruses. These viruses recognize and enter cells of non-rodent species by means of the cell-surface xenotropic and polytropic murine leukemia virus receptor (XPR1).
Judy Mikovits of the Whittemore Peterson Institute
has stated that XMRV has "almost certainly entered the U.S. blood supply system, but did not know whether it would be susceptible to the same heat treatments that successfully kill off the AIDS virus in blood products." Only fractionated plasma
is heat treated, blood for transfusion is not. A United States
federal consortium is now working to determine the prevalence of XMRV in the blood supply and the suitability of different detection methods. The preliminary phase of this project yielded inconclusive data. Although four patients tested positive at two of the sites, no patient was positive after repeated testing.
The association of XMRV and CFS reported in Science prompted Health Canada
, the New Zealand Blood Service, the Australian Red Cross Blood Service
, and the American Red Cross
in 2010, to disallow blood donations from individuals with CFS. On June 18, 2010, the American Association of Blood Banks, recommended actively discouraging potential donors who have been diagnosed by a physician as having CFS from donating blood or blood components.
As of November 1, 2010 people with CFS are no longer able to donate blood in the UK.
Writing in Cell Host & Microbe
, retrovirologists Mark Wainberg
and Kuan-Teh Jeang argue that a "scrupulously cautious" risk-benefit analysis is needed to assess the benefits and costs of testing or discarding blood on the basis of XMRV-positive results, taking into account the fact that some individuals and companies could profit from mandatory testing. They draw a parallel with the recent MMR-autism scare
, in which conflicts of interest played a role.
Gammaretrovirus
A gammaretrovirus is a genus of the retroviridae family. Example species are the murine leukemia virus and the feline leukemia virus.Many endogenous retroviruses, closely related to exogenous gammaretroviruses, are present in the DNA of mammals , birds, reptiles and amphibians.Many of the...
that was first described in 2006. Initial reports linked the virus to prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, and later to chronic fatigue syndrome
Chronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
(CFS), but these were followed by a large number of studies in which no association was found. It has not been established that XMRV can infect humans, nor has it been demonstrated that XMRV is associated with or causes human disease. Numerous researchers have suggested that XMRV detection may result from contamination of clinical specimens and laboratory reagents with mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
es or related nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
s. Nevertheless, public health officials have voiced concerns about the donated blood
Blood donation
A blood donation occurs when a person voluntarily has blood drawn and used for transfusions or made into medications by a process called fractionation....
supply, citing the potential dangers should XMRV prove to be an infectious human pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
.
Classification and genome
XMRV belongs to the virus family Retroviridae and the genus gammaretrovirusGammaretrovirus
A gammaretrovirus is a genus of the retroviridae family. Example species are the murine leukemia virus and the feline leukemia virus.Many endogenous retroviruses, closely related to exogenous gammaretroviruses, are present in the DNA of mammals , birds, reptiles and amphibians.Many of the...
. It has a single-stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
that replicates through a DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
intermediate. Its name refers to its close relationship with the murine leukemia virus
Murine leukemia virus
The murine leukemia viruses are retroviruses named for their ability to cause cancer in murine hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses...
es (“MuLVs”). The genome, approximately 8100 nucleotides in length, is 95% identical with several endogenous retrovirus
Endogenous retrovirus
Endogenous retroviruses are sequences in the genome thought to be derived from ancient viral infections of germ cells in humans, mammals and other vertebrates; as such their proviruses are passed on to the next generation and now remain in the genome....
es of mice, and is 93-94% identical with several exogenous
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
mouse viruses.
Several XMRV genomic sequences have been published to date. These sequences are almost identical, an unusual finding as retroviruses replicate their genomes with relatively low fidelity, leading to divergent viral sequences in a single host organism. The results of phylogenetic analyses of XMRV and related murine retroviruses led a group of researchers to conclude that XMRV "might not be a genuine human pathogen".
History
XMRV was discovered by laboratories led by Joseph DeRisiJoseph DeRisi
Joseph DeRisi is an American biochemist, specializing in molecular biology, parasitology, genomics, virology, and computational biology.He received a B.A. in Biochemistry and Molecular Biology from the University of California, Santa Cruz, and a Ph.D...
at the University of California, San Francisco
University of California, San Francisco
The University of California, San Francisco is one of the world's leading centers of health sciences research, patient care, and education. UCSF's medical, pharmacy, dentistry, nursing, and graduate schools are among the top health science professional schools in the world...
, and Robert Silverman and Eric Klein of the Cleveland Clinic
Cleveland Clinic
The Cleveland Clinic is a multispecialty academic medical center located in Cleveland, Ohio, United States. The Cleveland Clinic is currently regarded as one of the top 4 hospitals in the United States as rated by U.S. News & World Report...
. Silverman had previously cloned
Molecular cloning
Molecular cloning refers to a set of experimental methods in molecular biology that are used to assemble recombinant DNA molecules and to direct their replication within host organisms...
and investigated the enzyme ribonuclease L
RNAse L
RNase L is an interferon-induced ribonuclease which, upon activation, destroys all RNA within the cell .- Production and Activation :...
(RNase L), part of the cell’s natural defense against viruses. When activated, RNase L degrades cellular and viral RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
to halt viral replication. In 2002, the “hereditary prostate cancer 1” locus (HPC1) was mapped to the RNase L gene, implicating it in the development of prostate cancer. The cancer-associated “R462Q” mutation results in a glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
instead of an arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
at position 462 of the RNase L enzyme, reducing its catalytic activity. A man with two copies of this mutation has twice the risk of prostate cancer; one copy raises the risk by 50%.
Klein and Silverman hypothesized that “the putative linkage of RNase L alterations to HPC might reflect enhanced susceptibility to a viral agent”, leading to the discovery of XMRV.
Prostate cancer
Reports in the scientific literature have offered evidence both for and against an association of XMRV and prostate cancer. In the initial report on XMRV, the virus was detected in cancerous prostate tissues using a microarrayMicroarray
A microarray is a multiplex lab-on-a-chip. It is a 2D array on a solid substrate that assays large amounts of biological material using high-throughput screening methods.Types of microarrays include:...
containing samples of genetic material from about 950 viruses. The screen indicated the presence of a gammaretrovirus-like sequence in seven of eleven tumours homozygous for the R462Q mutation, but only in one of five tumours without the mutation. After isolation and cloning of the virus, an expanded screen found it present in 40% of tumours homozygous for R462Q and in only 1.5% of those not. A 2009 study reported evidence of XMRV infection in 23% of subjects independent of the RNase L gene variation, and detection of XMRV was again reported in a 2010 article.
However, numerous studies have failed to find evidence of XMRV in prostate cancer. Researchers in Germany found no XMRV-specific sequences in the DNA or RNA of samples from prostate cancer patients, and no XMRV-specific antibodies were detected in blood serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
samples. Another German study found no XMRV association with non-familial (sporadic) prostate cancer, and no XMRV link was found in Irish prostate cancer patients with the R462Q mutation. Similar results were reported in The Netherlands, Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, and Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
. Geographical differences were initially suspected as the culprit in these discrepancies, because the positive results were obtained in the United States. However, U.S. studies have also found no evidence of XMRV. Researchers at the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
, Johns Hopkins and the Mayo Clinic tested over 1,000 samples from prostate cancer patients but found no evidence of the virus.
A causal role of XMRV in cancer has not been established, and XMRV does not appear to be capable of transforming cells
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
directly. In prostate cancer, XMRV protein has been found in tumour-associated but nonmalignant stromal cell
Stromal cell
In cell biology, stromal cells are connective tissue cells of any organ, for example in the uterine mucosa , prostate, bone marrow, and the ovary. They are cells that support the function of the parenchymal cells of that organ...
s, but in one study is was not found in the actual prostate cancer cells, raising the possibility that the virus may indirectly support tumorigenesis. However, in another study, XMRV proteins and nucleic acids were found in malignant cells.
Chronic fatigue syndrome
In 2009, researchers reported finding XMRV DNA in two thirds of 101 people with chronic fatigue syndromeChronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
(CFS) but in only 4% of healthy controls. The authors, Lombardi et al., reported that patient-derived XMRV could infect cells in vitro and stated that "These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS". The reported association of XMRV and CFS, published in Science, generated worldwide media coverage and subsequent conflicting study results. Independent laboratories from around the world have not detected XMRV in CFS patient groups or control populations, using blood samples or cerebrospinal fluid. Various PCR assays and antibody-based detection methods were used in these investigations. Some of the authors of the original CFS report suggested that the widespread failure to replicate their results was attributable to different PCR conditions or to different criteria used to classify patients. However, several negative studies have been conducted with the same PCR primers used in the first investigation. Another study using the original reaction conditions did not detect XMRV in UK patients who "not only had CFS, but had considerable disability". Another study found no XMRV, but did report detection of murine leukemia virus
Murine leukemia virus
The murine leukemia viruses are retroviruses named for their ability to cause cancer in murine hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses...
related sequences in the blood of CFS patients. Two reviews have argued that reconciliation of these differences is necessary. The editor-in-chief of the journal Science in June 2011 published an expression of concern, stating that "the validity of the study by Lombardi et al. is now seriously in question". In September 2011, the original authors published a "Partial Retraction" of their 2009 findings, in which they acknowledged that "some of the CFS peripheral blood mononuclear cell (PBMC) DNA preparations are contaminated with XMRV plasmid DNA."
An international workshop was convened in September 2010 to aid in resolving the discrepancies. At the meeting, it was announced that Ian Lipkin
W. Ian Lipkin
W. Ian Lipkin is the John Snow Professor of Epidemiology at the Mailman School of Public Health at Columbia University and Professor of Neurology and Pathology at College of Physicians and Surgeons at Columbia University...
would oversee a multi-centre trial that would culminate in blinded testing of 150 CFS patients and 150 healthy but comparable donors by laboratories at the Whittemore Peterson Institute, the NIH and the CDC. The results of this multi-centre trial are expected to be available at the end of 2011.
Other conditions
XMRV has been proposed as a cause for conditions including autismAutism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
, multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
, and Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. However, there is currently no evidence to support these hypotheses. No XMRV was found in 230 autistic children or in 204 controls, nor was XMRV detected in fibromyalgia or MS patients or in children with idiopathic diseases. In one study, XMRV was detected in a small percentage of patients with weakened immune systems, but other studies found no evidence of XMRV in immunosuppression. Out of more than 500 HIV-1-positive people, none was positive for XMRV, nor was XMRV found in systemic lupus erythematosis patients.
Contamination and artifact
From the first reports of XMRV and disease associations, scientists were concerned that the positive findings could be artifactualArtifact (error)
In natural science and signal processing, an artifact is any error in the perception or representation of any visual or aural information introduced by the involved equipment or technique....
, for example as the result of contamination with nucleic acids from mice or mouse viruses. Most proposed retrovirus-disease associations have been prompted by accidental detection of contaminants, and initially promising results were later disproven or failed replication. Virologist Robin Weiss suggested in 2010 that XMRV is likely to be one of these "rumour viruses". The suspicion of contamination grew with an increasing number of negative studies as well as investigations demonstrating contamination.
The results of several studies support the contamination hypothesis. Scientists reported that they found ample sources of contamination in laboratory reagents, tissue samples and blood. Samples that were positive for XMRV were also positive for mouse DNA contaminants. Another article reported on the striking identity of XMRV genomic sequences and their similarity to xenotropic MLVs in several human cell lines. The authors conclude that XMRV contaminated 22Rv1 cell cultures, likely during passage in athymic mice
Nude mouse
A nude mouse is a laboratory mouse from a strain with a genetic mutation that causes a deteriorated or absent thymus, resulting in an inhibited immune system due to a greatly reduced number of T cells. The phenotype, or main outward appearance of the mouse is a lack of body hair, which gives it...
. (Production of laboratory cell lines may involve passaging of tumours in mice.) Identical XMRV integration sites were also found, a phenomenon never before reported for a retrovirus and strongly suggestive of contamination. It has been recommended that studies of XMRV should include more diverse and stringent PCR testing and phylogenetic analysis
Sequence alignment
In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Aligned sequences of nucleotide or amino acid residues are...
to detect occurrence of mouse DNA contamination from laboratory sources.
Responding to indications of contamination, the group that reported an association of XMRV with CFS stated that its evidence was not restricted to nucleic acids, but also included antibody-based detection. Their study used murine leukaemia virus antibodies and antigens, not XMRV-specific reagents. Multiple studies have failed to detect XMRV by PCR or antibody-based methods. In one study, several samples that were PCR-negative contained antibodies that interacted with XMRV. However, the authors found that these antibodies were non-specific and also interacted with other viruses. Mayo Clinic researchers also reported on non-specific anti-XMRV antibodies. In another study, only low reactivity with XMRV antigens was found, with no differences between cases and controls. The authors noted that establishing a cutoff for seropositivity was impossible, as no positive sera
Serum
Serum may refer to:*Blood serum, a component of blood which is collected after coagulation.**Antiserum, blood serum with specific antibodies for passive immunity*Serous fluid, any clear bodily fluid*any drug derived from an animal's blood or serous fluid...
are available. A study that included samples from the original XMRV-CFS report found no XMRV in patients or controls by PCR, antibody-based methods or viral culture. The authors discovered that some PCR reagents were contaminated with low levels of mouse nucleic acid but pointed out that this could not explain the high XMRV positive rates reported initially.
Blood supply controversy
Transmission of XMRV to or between humans has not been documented. Speculated modes of transmission include sexual and airborne routes, but the mode of human transmission, if any, has not yet been investigated. A study in the NetherlandsNetherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...
found no XMRV in the semen of HIV-positive men. Both cell-associated and cell-free transmission have been reported in vitro. XMRV is closely related to several known xenotropic mouse viruses. These viruses recognize and enter cells of non-rodent species by means of the cell-surface xenotropic and polytropic murine leukemia virus receptor (XPR1).
Judy Mikovits of the Whittemore Peterson Institute
Whittemore Peterson Institute
The Whittemore Peterson Institute for Neuro-Immune Disease is a research institute and charitable foundation known for its claims that the retrovirus xenotropic murine leukemia virus-related virus is associated with and may cause chronic fatigue syndrome and a variety of additional diseases...
has stated that XMRV has "almost certainly entered the U.S. blood supply system, but did not know whether it would be susceptible to the same heat treatments that successfully kill off the AIDS virus in blood products." Only fractionated plasma
Blood plasma fractionation
Blood plasma fractionation refers to the general processes of separating the various components of blood plasma, which in turn is a component of blood obtained through blood fractionation.-Blood plasma:...
is heat treated, blood for transfusion is not. A United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
federal consortium is now working to determine the prevalence of XMRV in the blood supply and the suitability of different detection methods. The preliminary phase of this project yielded inconclusive data. Although four patients tested positive at two of the sites, no patient was positive after repeated testing.
The association of XMRV and CFS reported in Science prompted Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies:Health Canada...
, the New Zealand Blood Service, the Australian Red Cross Blood Service
Australian Red Cross Blood Service
The Australian Red Cross Blood Service is a branch of the Australian Red Cross. It is the body primarily responsible for blood donation and related services in Australia.-History:...
, and the American Red Cross
American Red Cross
The American Red Cross , also known as the American National Red Cross, is a volunteer-led, humanitarian organization that provides emergency assistance, disaster relief and education inside the United States. It is the designated U.S...
in 2010, to disallow blood donations from individuals with CFS. On June 18, 2010, the American Association of Blood Banks, recommended actively discouraging potential donors who have been diagnosed by a physician as having CFS from donating blood or blood components.
As of November 1, 2010 people with CFS are no longer able to donate blood in the UK.
Writing in Cell Host & Microbe
Cell Host & Microbe
Cell Host & Microbe is a peer-reviewed scientific journal published by Cell Press. The journal was first launched in March 2007 and focuses broadly on the study of microbes, with an emphasis on the interface between the microbe and its host. The journal is run by in-house editorial and production...
, retrovirologists Mark Wainberg
Mark Wainberg
Mark A. Wainberg, is a Canadian AIDS researcher and activist. He is the Director of the McGill University AIDS Centre at the Montreal Jewish General Hospital and Professor of Medicine and of Microbiology at McGill University. His laboratory primarily studies HIV reverse transcriptase, and the...
and Kuan-Teh Jeang argue that a "scrupulously cautious" risk-benefit analysis is needed to assess the benefits and costs of testing or discarding blood on the basis of XMRV-positive results, taking into account the fact that some individuals and companies could profit from mandatory testing. They draw a parallel with the recent MMR-autism scare
MMR vaccine controversy
The MMR vaccine controversy was a case of scientific misconduct which triggered a health scare. It followed the publication in 1998 of a paper in the medical journal The Lancet which presented apparent evidence that autism spectrum disorders could be caused by the MMR vaccine, an immunization...
, in which conflicts of interest played a role.