Wikisage, the free encyclopedia of the second generation, is digital heritage
Xenotropic murine leukemia virus-related virus
Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus that was first described in 2006. XMRV has been isolated from human biological samples. Several reports have associated the virus with familial and sporadic prostate cancer, but other reports do not find a link. Similarly, a 2009 publication reported a possible association with chronic fatigue syndrome, but three other studies found no evidence of XMRV in patients or controls. It has not yet been established whether XMRV is a cause of either disease. A German study found XMRV in 2%-3% of healthy controls and 10% of immunocompromised patients.
Classification and genome
XMRV belongs to the virus family Retroviridae and the genus gammaretrovirus. It has a single-stranded RNA genome that replicates through a DNA intermediate. Its name refers to its close relationship with the murine leukemia viruses (“MuLVs”). The genome, approximately 8100 nucleotides in length, is 95% identical with several endogenous retroviruses 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.
XMRV was discovered by laboratories led by Joseph DeRisi 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%.
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.
Reported disease associations and transmission
Current reports in the scientific literature offer 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 microarray 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. Additionally, a 2009 study reported XMRV infection in 23% of subjects independent of the RNase L gene variation.
However, researchers in Germany failed to find any 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.
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 cells, but not 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, the Whittemore Peterson Institute , National Cancer Institute and Cleveland Clinic reported a possible association of XMRV with chronic fatigue syndrome. The study authors hypothesised that XMRV could cause CFS or be a passenger co-infection. Three follow-up studies failed to find evidence of XMRV in any of several hundred CFS patients or controls. Two reviews state reconciliation of these differences is necessary to investigate XMRV pathophysiology and treatment in CFS, and other possible XMRV-related illnesses, if they exist. The reported association of XMRV and CFS has generated media coverage and controversy amongst scientists and CFS patients alike.
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). Several authors have speculated that XMRV could be sexually transmitted, but the mode of human transmission, if any, has not yet been investigated. Both cell-associated and cell-free transmission have been reported in vitro. The virus has also been found in respiratory tracts and respiratory secretions of infected individuals
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." 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 association of XMRV and CFS reported in Science prompted Health Canada and The Australian Red Cross Blood Service in 2010, to disallow blood donations from individuals with CFS.
A study in the Public Library of Science (PLoS) in 2010 concluded that four anti-HIV drugs also inhibit XMRV replication. The drugs were two retroviral integrase inhibitors; raltegravir (Merck & Co., brand name Isentress), L-000870812 (Merck & Co.), and two nucleoside reverse transcriptase inhibitors; tenofovir disoproxil fumarate (Gilead Sciences, brand name Viread), and zidovudine (GlaxoSmithKline, azidothymidine (AZT)). Synergistic effects were reported when the drugs were used in combination.
- Urisman A, Molinaro RJ, Fischer N, et al. (March 2006). "Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant". PLoS Pathogens 2 (3): e25. doi:10.1371/journal.ppat.0020025. PMID 16609730.
- Silverman RH (2007). "A scientific journey through the 2-5A/RNase L system". Cytokine & Growth Factor Reviews 18 (5-6): 381–8. doi:10.1016/j.cytogfr.2007.06.012. PMID 17681844.
- Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR (September 2009). "XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors". Proceedings of the National Academy of Sciences of the United States of America 106 (38): 16351–6. doi:10.1073/pnas.0906922106. PMID 19805305.
- Hohn O, Krause H, Barbarotto P, et al. (2009). "Lack of evidence for xenotropic murine leukemia virus-related virus(XMRV) in German prostate cancer patients". Retrovirology 6: 92. doi:10.1186/1742-4690-6-92. PMID 19835577.
- Fischer N, Hellwinkel O, Schulz C, et al. (November 2008). "Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer". Journal of Clinical Virology 43 (3): 277–83. doi:10.1016/j.jcv.2008.04.016. PMID 18823818.
- Lombardi VC, Ruscetti FW, Das Gupta J, et al. (October 2009). "Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome". Science 326 (5952): 585–9. doi:10.1126/science.1179052. PMID 19815723.
- Erlwein O, Kaye S, McClure MO, et al. (2010). "Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome". PLoS ONE 5 (1): e8519. doi:10.1371/journal.pone.0008519. PMID 20066031.
- Groom, Harriet C T; Boucherit, Virginie C; Makinson, Kerry; Randal, Edward; Baptista, Sarah; Hagan, Suzanne; Gow, John W; Mattes, Frank M et al. (2010). "Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome". Retrovirology 7: 10. doi:10.1186/1742-4690-7-10. PMID 20156349.
- van Kuppeveld FJ, Jong AS, Lanke KH, et al. (2010). "Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort". BMJ 340: c1018. doi:10.1136/bmj.c1018. PMID 20185493. PMC 2829122. http://www.bmj.com/cgi/content/full/340/feb25_1/c1018.
- Lee K, Jones KS (February 2010). "The path well traveled: using mammalian retroviruses to guide research on XMRV". Molecular Interventions 10 (1): 20–4. doi:10.1124/mi.10.1.5. PMID 20124560.
- Voisin V, Rassart E (May 2007). "Complete genome sequences of the two viral variants of the Graffi MuLV: phylogenetic relationship with other murine leukemia retroviruses". Virology 361 (2): 335–47. doi:10.1016/j.virol.2006.10.045. PMID 17208267.
- Carpten J, Nupponen N, Isaacs S, et al. (February 2002). "Germline mutations in the ribonuclease L gene in families showing linkage with HPC1". Nature Genetics 30 (2): 181–4. doi:10.1038/ng823. PMID 11799394.
- D'Arcy F, Foley R, Perry A, et al. (March 2008). "No evidence of XMRV in Irish prostate cancer patients with the R462Q mutation". European Urology Supplements 7: 271. doi:10.1016/S1569-9056(08)60798-8.
- Metzger MJ, Holguin CJ, Mendoza R, Miller AD (February 2010). "The prostate cancer-associated human retrovirus XMRV lacks direct transforming activity but can induce low rates of transformation in cultured cells". Journal of Virology 84 (4): 1874–80. doi:10.1128/JVI.01941-09. PMID 20007266.
- McLaughlin-Drubin ME, Munger K (March 2008). "Viruses associated with human cancer". Biochimica et Biophysica Acta 1782 (3): 127–50. doi:10.1016/j.bbadis.2007.12.005. PMID 18201576.
- Baraniuk, James N (7 April 2010). "Xenotropic Murine Leukemia Virus-Related Virus in Chronic Fatigue Syndrome and Prostate Cancer". Current Allergy and Asthma Reports (Current Medicine Group LLC) 10: 210. doi:10.1007/s11882-010-0106-2. ISSN 1529-7322. http://www.springerlink.com/content/416lq773u356024x/. Retrieved 2010-04-25.
- Silverman, R. "The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome", Nature Reviews Urology, 1 June 2010.
- Hong S, Klein EA, Das Gupta J, et al. (July 2009). "Fibrils of prostatic acid phosphatase fragments boost infections with XMRV (xenotropic murine leukemia virus-related virus), a human retrovirus associated with prostate cancer". Journal of Virology 83 (14): 6995–7003. doi:10.1128/JVI.00268-09. PMID 19403677.
- Brower V (May 2009). "Is a retrovirus implicated in familial prostate cancer?". Journal of the National Cancer Institute 101 (10): 700–1. doi:10.1093/jnci/djp137. PMID 19436028.
- Eastman, Peggy (January 2009). "Prostate Cancer: New Data Help Refine Risk Stratification". Oncology Times 31 (2): 32–3. doi:10.1097/01.COT.0000345494.12042.f8 (inactive 2010-02-20). http://journals.lww.com/oncology-times/Fulltext/2009/01250/Prostate_Cancer__New_Data_Help_Refine_Risk.12.aspx.
- Virus leads Canadian Blood Services to ban certain donors Joseph Hall, The Hamilton Spectator, 06 April 2010.
- National Center for Preparedness, Detection, and Control of Infectious Diseases (NCPDCID). "Xenotropic Murine Leukemia Virus-related Virus (XMRV)". http://www.cdc.gov/ncidod/dhqp/bp_xmrv.html.
- Canadian Blood Services Responds to Possible New Blood Safety Threat
- Blood Service updates CFS donor policy
- Singh IR, Gorzynski JE, Drobysheva D, Bassit L, Schinazi RF, 2010 Raltegravir Is a Potent Inhibitor of XMRV, a Virus Implicated in Prostate Cancer and Chronic Fatigue Syndrome PLoS ONE 5(4): e9948. doi:10.1371/journal.pone.0009948