Biology:Xenotropic murine leukemia virus–related virus

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Short description: Species of virus


Xenotropic murine leukemia virus-related virus
Xmrv.gif
Virus classification e
(unranked): Virus
Realm: Riboviria
Kingdom: Pararnavirae
Phylum: Artverviricota
Class: Revtraviricetes
Order: Ortervirales
Family: Retroviridae
Genus: Gammaretrovirus
Virus:
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 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] and had been 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] These findings raised serious questions concerning the findings of XMRV-related studies which purported to find connections between XMRV and human diseases.[8] (As of 2022), there is no evidence that XMRV infects humans, nor that XMRV is associated with or causes any human disease.[9][10][11]

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.[12] 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.[citation needed] Several XMRV genomic sequences have been published to date. These sequences are almost identical, an unusual finding[13] as retroviruses replicate their genomes with relatively low fidelity, leading to divergent viral sequences in a single host organism.[13][14] 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".[15][8] 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.[16][17]

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.[18] 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%.[19] 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,[19] leading to the discovery of XMRV.

Disease association studies

Prostate cancer

Detection of XMRV was reported in several articles.[2][20] However, subsequent studies and retractions cast doubt on these findings.[21][22]

Other conditions

In one study, XMRV was detected in a small percentage of patients with weakened immune systems,[23] but other studies found no evidence of XMRV in immunosuppression.[24][25]

Controversy and origins

Concerns arose as multiple subsequent studies failed to replicate the positive findings of XMRV in the blood of patients with CFS, prostate cancer, and other illnesses.[26][8][27][28]

Separate from these concerns, alarms were raised over the possibility that XMRV might be transmissible by blood transfusion since the virus was recovered from lymphocytes (white blood cells).[29] XMRV is closely related to several known xenotropic mouse viruses which can recognize and enter cells of non-rodent species (including humans) by means of the cell surface xenotropic and polytropic retrovirus receptor 1 (XPR1).[30] As a result, the AABB (formerly the American Association of Blood Banks) established a task force to determine the prevalence of XMRV in the United States' blood donation supply and the suitability of different detection methods.[29]

In September 2011, the Scientific Research Working Group (SRWG) arm of the AABB task force released its findings that current assays could not reliably identify XMRV in human blood samples which had previously tested as XMRV/MLV positive; the only two labs which reported positive findings of XMRV in samples which were previously reported as positive (the WPI and NCI/Ruscetti labs) also reported positive findings in samples which were known XMRV negative.[31]

Multiple contemporary studies concluded that XMRV was most likely a result of incidental recombination of mouse viruses during prostate cancer research in the 1990s. Positive findings of the virus were likely due to contamination rather than true presence of the virus in humans.[8][3][5][4] A subsequent analysis also found that the primers used to detect and replicate traces of XMRV in PCR testing are, in fact, neither selective nor specific to XMRV and will actually react to various non-XMRV sequences naturally found in mammalian genomes.[32] In the meantime, multiple other studies also failed to find any link between XMRV and CFS or prostate cancer.[33][34][35] As a result, many of the key publications which did claim an association were voluntarily retracted.[2][36][21] This included the initial study which had linked XMRV to CFS, which was retracted at Silverman's request; one of the co-authors, Judy Mikovits, was also accused of scientific misconduct.[37][38][39]

References

  1. ↑ "XMRV (Xenotropic Murine Leukemia Virus-related Virus) | CDC" (in en-us). https://www.cdc.gov/xmrv/. 
  2. ↑ 2.0 2.1 2.2 Urisman, A.; Molinaro, R.J.; Fischer, N.; Plummer, S.J.; Casey, G.; Klein, E.A.; Malathi, K.; Magi-Galluzzi, C. et al. (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. PMID 16609730.  (Retracted, see doi:10.1371/annotation/7e2efc01-2e9b-4e9b-aef0-87ab0e4e4732)
  3. ↑ 3.0 3.1 3.2 "Origins of XMRV deciphered, undermining claims for a role in human disease", National Cancer Institute (NCI), 31 May 2011, http://www.cancer.gov/news-events/press-releases/2011/XMRVrecombination, retrieved 16 November 2015 
  4. ↑ 4.0 4.1 4.2 4.3 "NCI's Vinay K. Pathak on the "De-Discovery" of a Retrovirus-Disease Link", Science Watch, Fast Breaking Papers, 2012, http://archive.sciencewatch.com/dr/fbp/2012/parthak-vinay/, retrieved 16 November 2015 
  5. ↑ 5.0 5.1 5.2 5.3 Paprotka, Tobias; Delviks-Frankenberry, Krista A.; Cingöz, Oya; Martinez, Anthony; Hsing-Jien, Kung; Tepper, Clifford G.; Wei-Shau, Hu; Fivash Jr., Matthew J. et al. (1 July 2011). "Recombinant origin of the retrovirus XMRV". Science 333 (6038): 97–101. doi:10.1126/science.1205292. ISSN 0036-8075. PMID 21628392. Bibcode: 2011Sci...333...97P.  via EBSCO login
  6. ↑ "Definition of xenotropic". https://www.merriam-webster.com/dictionary/xenotropic. 
  7. ↑ "Definition of murine". https://www.merriam-webster.com/dictionary/murine. 
  8. ↑ 8.0 8.1 8.2 8.3 Smith RA (December 2010). "Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses". Retrovirology 7 (1): 112. doi:10.1186/1742-4690-7-112. PMID 21171980. PMC 3022688. http://www.retrovirology.com/content/pdf/1742-4690-7-112.pdf. 
  9. ↑ Arias, Maribel; Fan, Hung (January 2014). "The saga of XMRV: a virus that infects human cells but is not a human virus". Emerging Microbes & Infections 3 (1): e. doi:10.1038/emi.2014.25. PMID 26038516. 
  10. ↑ "XMRV (Xenotropic Murine Leukemia Virus-related Virus) Updates". 23 August 2010. https://www.cdc.gov/xmrv/updates.html. 
  11. ↑ "Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and other Polytropic Murine Leukemia Viruses (pMLV)". October 2012. https://www.aabb.org/docs/default-source/default-document-library/regulatory/eid/xmrvfactsheet.pdf?sfvrsn=cd162fa3_2. 
  12. ↑ 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. PMID 22031947. 
  13. ↑ 13.0 13.1 "The path well traveled: using mammalian retroviruses to guide research on XMRV". Molecular Interventions 10 (1): 20–4. February 2010. doi:10.1124/mi.10.1.5. PMID 20124560. 
  14. ↑ "Complete genome sequences of the two viral variants of the Graffi MuLV: phylogenetic relationship with other murine leukemia retroviruses". Virology 361 (2): 335–47. May 2007. doi:10.1016/j.virol.2006.10.045. PMID 17208267. 
  15. ↑ 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. PMID 21171979. 
  16. ↑ Levy, Jay A. (14 December 1973). "Xenotropic Viruses: Murine Leukemia Viruses Associated with NIH Swiss, NZB, and Other Mouse Strains". Science 182 (4117): 1151–1153. doi:10.1126/science.182.4117.1151. PMID 4356281. Bibcode: 1973Sci...182.1151L. 
  17. ↑ Levy, Jay A. (1978). "Xenotropic Type C Viruses". Curr Top Microbiol Immunol. Modern Aspects of Electrochemistry 79: 111–213. doi:10.1007/978-3-642-66853-1_4. ISBN 978-1-4612-9003-2. PMID 77206. 
  18. ↑ "Germline mutations in the ribonuclease L gene in families showing linkage with HPC1". Nature Genetics 30 (2): 181–4. February 2002. doi:10.1038/ng823. PMID 11799394. https://zenodo.org/record/1233415. 
  19. ↑ 19.0 19.1 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. 
  20. ↑ 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. 
  21. ↑ 21.0 21.1 Schlaberg, R; Choe, DJ; Brown, KR; Thaker, HM; Singh, IR (22 September 2009). "XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors". PNAS 106 (38): 16351–16356. doi:10.1073/pnas.0906922106. PMID 19805305. Bibcode: 2009PNAS..10616351S.  (Retracted, see doi:10.1073/pnas.1409186111)
  22. ↑ Lee, Deanna; Das Gupta, Jaydip; Gaughan, Christina; Steffen, Imke; Tang, Ning; Luk, Ka-Cheung; Qiu, Xiaoxing; Urisman, Anatoly et al. (18 September 2012). "In-Depth Investigation of Archival and Prospectively Collected Samples Reveals No Evidence for XMRV Infection in Prostate Cancer". PLoS ONE 7 (9): e44954. doi:10.1371/journal.pone.0044954. PMID 23028701. Bibcode: 2012PLoSO...744954L. 
  23. ↑ "Xenotropic murine leukemia virus-related gammaretrovirus in respiratory tract". Emerg Infect Dis 16 (6): 1000–2. June 2010. doi:10.3201/eid1606.100066. PMID 20507757.  PDF: https://www.cdc.gov/eid/content/16/6/pdfs/1000.pdf
  24. ↑ 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. PMID 20936980. 
  25. ↑ 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. 
  26. ↑ van der Kuyl, Antoinette Cornelia; Cornelissen, Marion; Berkhout, Ben (2011). "Of Mice and Men: On the Origin of XMRV". Frontiers in Microbiology 1: 147. doi:10.3389/fmicb.2010.00147. PMID 21687768. 
  27. ↑ "Published Studies on XMRV and pMLV Findings in Human Diseases and the General Population". September 2012. https://www.aabb.org/docs/default-source/default-document-library/regulatory/eid/xmrvtable.pdf?sfvrsn=badfef36_2. 
  28. ↑ Dodd, R. Y. (December 2011). "XMRV and blood safety: a case study of science and public pressure: XMRV and blood safety". ISBT Science Series 6 (2): 446–448. doi:10.1111/j.1751-2824.2011.01538.x. 
  29. ↑ 29.0 29.1 "Xenotropic murine leukemia virus-related virus (XMRV) and blood transfusion: report of the AABB interorganizational XMRV task force". Transfusion 51 (3): 654–61. 2011. doi:10.1111/j.1537-2995.2010.03012.x. PMID 21235597. https://zenodo.org/record/1230675. 
  30. ↑ Kozak, CA (2010). "The mouse "xenotropic" gammaretroviruses and their XPR1 receptor". Retrovirology 7: 101. doi:10.1186/1742-4690-7-101. PMID 21118532. 
  31. ↑ Simmons, Graham; Glynn, Simone A.; Komaroff, Anthony L.; Mikovits, Judy A.; Tobler, Leslie H.; Hackett, John; Tang, Ning; Switzer, William M. et al. (11 November 2011). "Failure to Confirm XMRV/MLVs in the Blood of Patients with Chronic Fatigue Syndrome: A Multi-Laboratory Study". Science 334 (6057): 814–817. doi:10.1126/science.1213841. PMID 21940862. Bibcode: 2011Sci...334..814S. 
  32. ↑ Panelli, Simona; Lorusso, Lorenzo; Balestrieri, Alessandro; Lupo, Giuseppe; Capelli, Enrica (22 May 2017). "XMRV and Public Health: The Retroviral Genome Is Not a Suitable Template for Diagnostic PCR, and Its Association with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Appears Unreliable". Frontiers in Public Health 5: 108. doi:10.3389/fpubh.2017.00108. PMID 28589117. 
  33. ↑ Robinson, Mark J.; Erlwein, Otto; McClure, Myra O. (November 2011). "Xenotropic murine leukaemia virus-related virus (XMRV) does not cause chronic fatigue". Trends in Microbiology 19 (11): 525–529. doi:10.1016/j.tim.2011.08.005. PMID 21978843. 
  34. ↑ Alter, Harvey J.; Mikovits, Judy A.; Switzer, William M.; Ruscetti, Francis W.; Lo, Shyh-Ching; Klimas, Nancy; Komaroff, Anthony L.; Montoya, Jose G. et al. (November 2012). "A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus". mBio 3 (5): e00266–12. doi:10.1128/mBio.00266-12. PMID 22991430. 
  35. ↑ Sfanos, Karen S.; Aloia, Amanda L.; De Marzo, Angelo M.; Rein, Alan (February 2012). "XMRV and prostate cancer—a 'final' perspective". Nature Reviews Urology 9 (2): 111–118. doi:10.1038/nrurol.2011.225. PMID 22231291. 
  36. ↑ Lo, SC; Pripuzova, N; Li, B; Komaroff, AL; Hung, GC; Wang, R; Alter, HJ (7 September 2010). "Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors.". PNAS 107 (36): 15874–9. doi:10.1073/pnas.1006901107. PMID 20798047. Bibcode: 2010PNAS..10715874L.  (Retracted, see doi:10.1073/pnas.1119641109)
  37. ↑ Lombardi, Vincent C.; Ruscetti, Francis W.; Das Gupta, Jaydip; Pfost, Max A.; Hagen, Kathryn S.; Peterson, Daniel L.; Ruscetti, Sandra K.; Bagni, Rachel K. et al. (23 October 2009). "Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome". Science 326 (5952): 585–589. doi:10.1126/science.1179052. PMID 19815723. Bibcode: 2009Sci...326..585L.  (Retracted, see doi:10.1126/science.334.6063.1636-a)
  38. ↑ Cohen, Jon (22 December 2011). "UPDATED: In a Rare Move, Science Without Authors' Consent Retracts Paper That Tied Mouse Virus to Chronic Fatigue Syndrome". https://www.science.org/content/article/updated-rare-move-science-without-authors-consent-retracts-paper-tied-mouse-virus. 
  39. ↑ Tsouderos, Trine (October 3, 2011). "Manipulation alleged in paper linking virus, chronic fatigue syndrome". Chicago Tribune. https://www.chicagotribune.com/health/chi-chronic-fatigue-syndrome-paper-10032011,0,6792877.story. 

External links

Wikidata ☰ Q1855214 entry



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