Xenotropic murine leukemia virus-related virus

Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus which was first described in 2006 as an apparently novel human pathogen found in tissue samples from men with prostate cancer.[1][2] Initial reports erroneously linked the virus to prostate cancer and later to chronic fatigue syndrome (CFS), leading to considerable interest in the scientific and patient communities, investigation of XMRV as a potential cause of multiple medical conditions, and public-health concerns about the safety of the donated blood supply.[3][4][5]

Xenotropic murine leukemia virus-related virus
Virus classification
Group:
Group VI (ssRNA-RT)
Order:
Ortervirales
Family:
Retroviridae
Subfamily:
Orthoretrovirinae
Genus:
Gammaretrovirus
Species:
Xenotropic MuLV-related virus

Xenotropic viruses replicate or reproduce in cells other than those of the host species.[6] Murine refers to the rodent family Muridae, which includes common household rats and mice.[7]

Subsequent research established that XMRV was in fact a laboratory contaminant, rather than a novel pathogen.[4][5] XMRV was generated unintentionally in the laboratory, through genetic recombination between two mouse retroviruses during propagation of a prostate-cancer cell line in the mid-1990s.[3][4][5] False-positive detection of XMRV may also occur because of contamination of clinical specimens and laboratory reagents with other mouse retroviruses or related nucleic acids. Most scientific publications claiming an association of XMRV with CFS or prostate cancer have been retracted, and allegations of research misconduct were leveled against at least one CFS investigator. There is no evidence that XMRV can infect humans, nor that XMRV is associated with or causes any human disease.

Classification and genome

XMRV is a murine leukemia virus (MLV) that formed through the recombination of the genomes of two parent MLVs known as preXMRV-1 and preXMRV-2.[8] MLVs belong to the virus family Retroviridae and the genus gammaretrovirus and have a single-stranded RNA genome that replicates through a DNA intermediate. The name XMRV was given because the discoverers of the virus initially thought that it was a novel potential human pathogen that was related to but distinct from MLVs. The XMRV particle is approximately spherical and 80 to 100 nm in diameter.Several XMRV genomic sequences have been published to date. These sequences are almost identical, an unusual finding[9] as retroviruses replicate their genomes with relatively low fidelity, leading to divergent viral sequences in a single host organism.[9][10] In 2010 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".[11][12] Xenotropic Murine Leukemia Virus-Related Virus: Classification Xenotropic viruses (xenos Gr. foreign; tropos Gr. turning) were initially discovered in the New Zealand Black (NZB) mouse and later found to be present in many other mouse strains including wild mice.[13][14]

Discovery

XMRV was discovered in the laboratories of 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.[15] 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%.[16] Klein and Silverman hypothesized that "the putative linkage of RNase L alterations to HPC might reflect enhanced susceptibility to a viral agent" and conducted a viral screen of prostate cancer samples,[16] leading to the discovery of XMRV.

Disease association studies

Prostate cancer

Detection of XMRV was reported in a 2010 article.[17]

Other conditions

In one study, XMRV was detected in a small percentage of patients with weakened immune systems,[18] but other studies found no evidence of XMRV in immunosuppression.[19][20]

Contamination and artifact

Initially promising results were later disproven or failed replication.[12]

Blood supply controversy

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).[21]

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.[22]

See also

References
  1. "XMRV (Xenotropic Murine Leukemia Virus-related Virus) | CDC". www.cdc.gov. Retrieved 2018-04-17.
  2. Urisman, A.; Molinaro, R.J.; Fischer, N.; Plummer, S.J.; Casey, G.; Klein, E.A.; Malathi, K.; Magi-Galluzzi, C.; Tubbs, R. R.; Ganem, D. (2006). "Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant". PLOS Pathog. 2 (3): e25. doi:10.1371/journal.ppat.0020025. PMC 1434790. PMID 16609730. (Retracted, see doi:10.1371/annotation/7e2efc01-2e9b-4e9b-aef0-87ab0e4e4732)
  3. "Origins of XMRV deciphered, undermining claims for a role in human disease", National Cancer Institute (NCI), 31 May 2011, archived from the original on 2015-11-17, retrieved 16 November 2015
  4. "NCI's Vinay K. Pathak on the "De-Discovery" of a Retrovirus-Disease Link", Science Watch, Fast Breaking Papers, 2012, retrieved 16 November 2015
  5. Paprotka, Tobias; Delviks-Frankenberry, Krista A.; Cingöz, Oya; Martinez, Anthony; Hsing-Jien, Kung; Tepper, Clifford G.; Wei-Shau, Hu; Fivash Jr., Matthew J.; Coffin, John M.; Pathak, Vinay K. (1 July 2011). "Recombinant origin of the retrovirus XMRV". Science. 333 (6038): 97–101. Bibcode:2011Sci...333...97P. doi:10.1126/science.1205292. ISSN 0036-8075. PMC 3278917. PMID 21628392. via EBSCO login
  6. "Definition of xenotropic". Merriam-Webster. Retrieved 2020-05-06.
  7. "Definition of murine". Merriam-Webster. Retrieved 2020-05-06.
  8. Cingöz, O; Paprotka, T; Delviks-Frankenberry, KA; Wildt, S; Hu, WS; Pathak, VK; Coffin, JM (2012). "Characterization, mapping, and distribution of the two XMRV parental proviruses". Journal of Virology. 86 (1): 328–38. doi:10.1128/JVI.06022-11. PMC 3255884. PMID 22031947.
  9. 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. PMC 2895355. PMID 20124560.
  10. 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.
  11. Hué, S; Gray, ER; Gall, A; Katzourakis, A; Tan, CP; Houldcroft, CJ; McLaren, S; Pillay, D; et al. (2010). "Disease-associated XMRV sequences are consistent with laboratory contamination". Retrovirology. 7 (1): 111. doi:10.1186/1742-4690-7-111. PMC 3018392. PMID 21171979.
  12. Smith RA (December 2010). "Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses" (PDF). Retrovirology. 7 (1): 112. doi:10.1186/1742-4690-7-112. PMC 3022688. PMID 21171980.
  13. Levy, J.A., Xenotropic viruses: murine leukemia viruses associated with NIH Swiss, NZB, and other mouse strains. Science, 1973. 182: p. 1151-1153.
  14. Levy, J.A., Xenotropic type C viruses. Current Topics in Microbiology and Immunology, 1978. 79: p. 111-213.
  15. 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.
  16. 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. PMC 2075094. PMID 17681844.
  17. Arnold, RS; Makarova, NV; Osunkoya, AO; Suppiah, S; Scott, TA; Johnson, NA; Bhosle, SM; Liotta, D; et al. (2010). "XMRV infection in patients with prostate cancer: novel serologic assay and correlation with PCR and FISH". Urology. 75 (4): 755–61. doi:10.1016/j.urology.2010.01.038. PMID 20371060.
  18. Fischer N, Schulz C, Stieler K, Hohn O, Lange C, Drosten C, Aepfelbacher M (June 2010). "Xenotropic murine leukemia virus-related gammaretrovirus in respiratory tract". Emerg Infect Dis. 16 (6): 1000–2. doi:10.3201/eid1606.100066. PMC 3086240. PMID 20507757. PDF: https://www.cdc.gov/eid/content/16/6/pdfs/1000.pdf Archived 2010-06-13 at the Wayback Machine
  19. Henrich, TJ; Li, JZ; Felsenstein, D; Kotton, CN; Plenge, RM; Pereyra, F; Marty, FM; Lin, NH; et al. (2010). "Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions". The Journal of Infectious Diseases. 202 (10): 1478–81. doi:10.1086/657168. PMC 2957553. PMID 20936980.
  20. Barnes, E; Flanagan, P; Brown, A; Robinson, N; Brown, H; McClure, M; Oxenius, A; Collier, J; et al. (2010). "Failure to detect xenotropic murine leukemia virus-related virus in blood of individuals at high risk of blood-borne viral infections". The Journal of Infectious Diseases. 202 (10): 1482–5. doi:10.1086/657167. PMID 20936982.
  21. Kozak, CA (2010). "The mouse "xenotropic" gammaretroviruses and their XPR1 receptor". Retrovirology. 7: 101. doi:10.1186/1742-4690-7-101. PMC 3009702. PMID 21118532.
  22. Klein HG, Dodd RY, Hollinger FB, Katz LM, Kleinman S, McCleary KK, Silverman RH, Stramer SL; AABB Interorganizational Task Force on XMRV (2011). "Xenotropic murine leukemia virus-related virus (XMRV) and blood transfusion: report of the AABB interorganizational XMRV task force". Transfusion. 51 (3): 654–61. doi:10.1111/j.1537-2995.2010.03012.x. PMID 21235597.CS1 maint: multiple names: authors list (link)


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