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Xenotropic murine leukemia virus–related virus

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Xenotropic murine leukemia virus-related virus
Virus classification Edit this classification
(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

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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

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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

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Prostate cancer

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

Other conditions

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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

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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

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  1. ^ "XMRV (Xenotropic Murine Leukemia Virus-related Virus) | CDC". Centers for Disease Control. Archived from the original on 18 April 2018. Retrieved 2018-04-17.
  2. ^ a b c 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, PMID 23028303,  Retraction Watch)
  3. ^ a b c "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. ^ a b c d "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. ^ a b c d Paprotka T, Delviks-Frankenberry KA, Cingöz O, Martinez A, Hsing-Jien K, Tepper CG, Wei-Shau H, Fivash Jr MJ, Coffin JM, Pathak VK (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. ^ a b c d 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.
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  17. ^ Levy JA (1978). "Xenotropic Type C Viruses". Modern Aspects of Electrochemistry. Vol. 79. pp. 111–213. doi:10.1007/978-3-642-66853-1_4. ISBN 978-1-4612-9003-2. PMID 77206. {{cite book}}: |journal= ignored (help)
  18. ^ 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. S2CID 2922306.
  19. ^ a b 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.
  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.
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  22. ^ Lee D, Das Gupta J, Gaughan C, Steffen I, Tang N, Luk KC, Qiu X, Urisman A, Fischer N, Molinaro R, Broz M, Schochetman G, Klein EA, Ganem D, DeRisi JL, Simmons G, Hackett J, Silverman RH, Chiu CY (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. Bibcode:2012PLoSO...744954L. doi:10.1371/journal.pone.0044954. PMC 3445615. PMID 23028701.
  23. ^ 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
  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. PMC 2957553. 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. hdl:20.500.11850/24494. PMID 20936982.
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  30. ^ 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.
  31. ^ Simmons G, Glynn SA, Komaroff AL, Mikovits JA, Tobler LH, Hackett J, Tang N, Switzer WM, Heneine W, Hewlett IK, Zhao J, Lo SC, Alter HJ, Linnen JM, Gao K, Coffin JM, Kearney MF, Ruscetti FW, Pfost MA, Bethel J, Kleinman S, Holmberg JA, Busch MP (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. Bibcode:2011Sci...334..814S. doi:10.1126/science.1213841. PMC 3299483. PMID 21940862.
  32. ^ Panelli S, Lorusso L, Balestrieri A, Lupo G, Capelli E (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. PMC 5439170. PMID 28589117.
  33. ^ Robinson MJ, Erlwein O, McClure MO (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 HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI (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. PMC 3448165. PMID 22991430.
  35. ^ Sfanos KS, Aloia AL, De Marzo AM, Rein A (February 2012). "XMRV and prostate cancer—a 'final' perspective". Nature Reviews Urology. 9 (2): 111–118. doi:10.1038/nrurol.2011.225. PMC 4029112. 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. Bibcode:2010PNAS..10715874L. doi:10.1073/pnas.1006901107. PMC 2936598. PMID 20798047. (Retracted, see doi:10.1073/pnas.1119641109, PMID 22203980,  Retraction Watch)
  37. ^ Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA (23 October 2009). "Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome". Science. 326 (5952): 585–589. Bibcode:2009Sci...326..585L. doi:10.1126/science.1179052. PMID 19815723. (Retracted, see doi:10.1126/science.334.6063.1636-a, PMID 22194552,  Retraction Watch)
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  39. ^ Tsouderos, Trine (October 3, 2011). "Manipulation alleged in paper linking virus, chronic fatigue syndrome". Chicago Tribune. Archived from the original on 28 October 2022.
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