Xenotropic murine leukemia virus–related virus explained

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.

Xenotropic viruses replicate or reproduce in cells other than those of the host species.[3] Murine refers to the rodent family Muridae, which includes common household rats and mice.[4]

Subsequent research established that XMRV was in fact a laboratory contaminant, rather than a novel pathogen, 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.[5] These findings raised serious questions concerning the findings of XMRV-related studies which purported to find connections between XMRV and human diseases., there is no evidence that XMRV infects humans, nor that XMRV is associated with or causes any human disease.[6] [7] [8]

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.[9] 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[10] as retroviruses replicate their genomes with relatively low fidelity, leading to divergent viral sequences in a single host organism.[10] [11] 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".[12] [13] 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.[14] [15]

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.[16] 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%.[17] 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,[17] leading to the discovery of XMRV.

Disease association studies

Prostate cancer

Detection of XMRV was reported in several articles.[2] [18] However, subsequent studies and retractions cast doubt on these findings.[19]

Other conditions

In one study, XMRV was detected in a small percentage of patients with weakened immune systems,[20] but other studies found no evidence of XMRV in immunosuppression.[21] [22]

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.[23] [13] [24] [25]

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).[26] 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).[27] 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.[26]

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.[28]

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.[13] [5] 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.[29] In the meantime, multiple other studies also failed to find any link between XMRV and CFS or prostate cancer.[30] [31] [32] As a result, many of the key publications which did claim an association were voluntarily retracted.[2] [33] [34] 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.[35] [36] [37]

External links

Notes and References

  1. Web site: XMRV (Xenotropic Murine Leukemia Virus-related Virus) CDC. Centers for Disease Control. en-us. 2018-04-17. dead . https://web.archive.org/web/20180418092917/https://www.cdc.gov/xmrv/ . 18 April 2018.
  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.. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. . 2006 . 2. e25 . 3. 10.1371/journal.ppat.0020025. 16609730 . 1434790 . free .
  3. Web site: Definition of xenotropic . Merriam-Webster . 2020-05-06 .
  4. Web site: Definition of murine . Merriam-Webster . 2020-05-06 .
  5. Recombinant origin of the retrovirus XMRV . . 1 July 2011 . 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. . 97–101 . 333 . 6038 . 0036-8075 . 10.1126/science.1205292 . 21628392 . 3278917 . 2011Sci...333...97P . vanc. via EBSCO login
  6. Arias . Maribel . Fan . Hung . The saga of XMRV: a virus that infects human cells but is not a human virus . Emerging Microbes & Infections . January 2014 . 3 . 1 . e . 10.1038/emi.2014.25 . 26038516 . 4008767 . vanc.
  7. Web site: XMRV (Xenotropic Murine Leukemia Virus-related Virus) Updates . . 5 March 2023 . https://web.archive.org/web/20180627055901/https://www.cdc.gov/xmrv/updates.html . 27 June 2018 . 23 August 2010 . dead.
  8. Web site: Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and other Polytropic Murine Leukemia Viruses (pMLV) . . 5 March 2023 . https://web.archive.org/web/20220706005436/https://www.aabb.org/docs/default-source/default-document-library/regulatory/eid/xmrvfactsheet.pdf?sfvrsn=cd162fa3_2 . 6 July 2022 . October 2012.
  9. 2012 . Characterization, mapping, and distribution of the two XMRV parental proviruses . . 86 . 1 . 328–38 . 22031947 . Cingöz . O . Paprotka . T . Delviks-Frankenberry . KA . Wildt . S . Hu . WS . Pathak . VK . Coffin . JM . 10.1128/JVI.06022-11 . 3255884.
  10. Lee K, Jones KS . The path well traveled: using mammalian retroviruses to guide research on XMRV . Molecular Interventions . 10 . 1 . 20–4 . February 2010 . 20124560 . 2895355 . 10.1124/mi.10.1.5.
  11. Voisin V, Rassart E . Complete genome sequences of the two viral variants of the Graffi MuLV: phylogenetic relationship with other murine leukemia retroviruses . . 361 . 2 . 335–47 . May 2007 . 17208267 . 10.1016/j.virol.2006.10.045. free .
  12. 21171979. 2010. Hué. S. Gray. ER. Gall. A. Katzourakis. A. Tan. CP. Houldcroft. CJ. McLaren. S. Pillay. D. Futreal. A. 8. Disease-associated XMRV sequences are consistent with laboratory contamination. 7. 1. 111. 10.1186/1742-4690-7-111. 3018392. . free .
  13. Smith RA . Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses . . 7 . 1 . 112 . December 2010 . 21171980 . 10.1186/1742-4690-7-112 . 3022688 . free .
  14. Levy . Jay A. . Jay A. Levy . Xenotropic Viruses: Murine Leukemia Viruses Associated with NIH Swiss, NZB, and Other Mouse Strains . . 14 December 1973 . 182 . 4117 . 1151–1153 . 10.1126/science.182.4117.1151 . 4356281 . 1973Sci...182.1151L . 22929896 . vanc.
  15. Book: Levy . Jay A. . Xenotropic Type C Viruses . Jay A. Levy . Modern Aspects of Electrochemistry . Curr Top Microbiol Immunol . 1978 . 79 . 111–213 . 10.1007/978-3-642-66853-1_4 . 77206 . 978-1-4612-9003-2 . vanc.
  16. Carpten J, Nupponen N, Isaacs S, etal . Germline mutations in the ribonuclease L gene in families showing linkage with HPC1 . . 30 . 2 . 181–4 . February 2002 . 11799394 . 10.1038/ng823. 2922306 .
  17. Silverman RH . A scientific journey through the 2-5A/RNase L system . Cytokine & Growth Factor Reviews . 18 . 5–6 . 381–8 . 2007 . 17681844 . 2075094 . 10.1016/j.cytogfr.2007.06.012.
  18. 20371060. 2010. Arnold. RS. Makarova. NV. Osunkoya. AO. Suppiah. S. Scott. TA. Johnson. NA. Bhosle. SM. Liotta. D. Hunter. E. 8. XMRV infection in patients with prostate cancer: novel serologic assay and correlation with PCR and FISH. 75. 4. 755–61. 10.1016/j.urology.2010.01.038. .
  19. Lee . Deanna . Das Gupta . Jaydip . Gaughan . Christina . Steffen . Imke . Tang . Ning . Luk . Ka-Cheung . Qiu . Xiaoxing . Urisman . Anatoly . Fischer . Nicole . Molinaro . Ross . Broz . Miranda . Schochetman . Gerald . Klein . Eric A. . Ganem . Don . DeRisi . Joseph L. . Simmons . Graham . Hackett . John . Silverman . Robert H. . Chiu . Charles Y. . In-Depth Investigation of Archival and Prospectively Collected Samples Reveals No Evidence for XMRV Infection in Prostate Cancer . . 18 September 2012 . 7 . 9 . e44954 . 10.1371/journal.pone.0044954 . 23028701 . 3445615 . 2012PLoSO...744954L . vanc . free .
  20. Fischer N, Schulz C, Stieler K, Hohn O, Lange C, Drosten C, Aepfelbacher M . Xenotropic murine leukemia virus-related gammaretrovirus in respiratory tract . . 16 . 6 . 1000–2 . June 2010 . 20507757 . 3086240 . 10.3201/eid1606.100066. PDF: https://www.cdc.gov/eid/content/16/6/pdfs/1000.pdf
  21. 20936980. 2010. Henrich. TJ. Li. JZ. Felsenstein. D. Kotton. CN. Plenge. RM. Pereyra. F. Marty. FM. Lin. NH. Grazioso. P. 8. Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions. 202. 10. 1478–81. 10.1086/657168. 2957553. The Journal of Infectious Diseases.
  22. 20936982. 2010. Barnes. E. Flanagan. P. Brown. A. Robinson. N. Brown. H. McClure. M. Oxenius. A. Collier. J. Weber. J. 8. Eleanor Barnes. Annette Oxenius. Failure to detect xenotropic murine leukemia virus-related virus in blood of individuals at high risk of blood-borne viral infections. 202. 10. 1482–5. 10.1086/657167. The Journal of Infectious Diseases. free. 20.500.11850/24494. free.
  23. van der Kuyl . Antoinette Cornelia . Cornelissen . Marion . Berkhout . Ben . Of Mice and Men: On the Origin of XMRV . Frontiers in Microbiology . 2011 . 1 . 147 . 10.3389/fmicb.2010.00147 . 21687768 . 3109487 . vanc . free .
  24. Web site: Published Studies on XMRV and pMLV Findings in Human Diseases and the General Population . . 5 March 2023 . https://web.archive.org/web/20220527161150/https://www.aabb.org/docs/default-source/default-document-library/regulatory/eid/xmrvtable.pdf?sfvrsn=badfef36_2 . 27 May 2022 . September 2012.
  25. Dodd . R. Y. . XMRV and blood safety: a case study of science and public pressure: XMRV and blood safety . ISBT Science Series . December 2011 . 6 . 2 . 446–448 . 10.1111/j.1751-2824.2011.01538.x . free.
  26. Klein HG, Dodd RY, Hollinger FB, Katz LM, Kleinman S, McCleary KK, Silverman RH, Stramer SL, ((AABB Interorganizational Task Force on XMRV)) . Xenotropic murine leukemia virus-related virus (XMRV) and blood transfusion: report of the AABB interorganizational XMRV task force . . 51 . 3 . 654–61 . 2011 . 21235597 . 10.1111/j.1537-2995.2010.03012.x. 31115745 . free.
  27. 21118532. 2010. Kozak. CA. The mouse "xenotropic" gammaretroviruses and their XPR1 receptor. 7. 101. 10.1186/1742-4690-7-101. 3009702. . free .
  28. Simmons . Graham . Glynn . Simone A. . Komaroff . Anthony L. . Mikovits . Judy A. . Tobler . Leslie H. . Hackett . John . Tang . Ning . Switzer . William M. . Heneine . Walid . Hewlett . Indira K. . Zhao . Jiangqin . Lo . Shyh-Ching . Alter . Harvey J. . Linnen . Jeffrey M. . Gao . Kui . Coffin . John M. . Kearney . Mary F. . Ruscetti . Francis W. . Pfost . Max A. . Bethel . James . Kleinman . Steven . Holmberg . Jerry A. . Busch . Michael P. . Failure to Confirm XMRV/MLVs in the Blood of Patients with Chronic Fatigue Syndrome: A Multi-Laboratory Study . . 11 November 2011 . 334 . 6057 . 814–817 . 10.1126/science.1213841 . 21940862 . 3299483 . 2011Sci...334..814S . vanc.
  29. Panelli . Simona . Lorusso . Lorenzo . Balestrieri . Alessandro . Lupo . Giuseppe . Capelli . Enrica . 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 . 22 May 2017 . 5 . 108 . 10.3389/fpubh.2017.00108 . 28589117 . 5439170 . vanc . free .
  30. Robinson . Mark J. . Erlwein . Otto . McClure . Myra O. . Xenotropic murine leukaemia virus-related virus (XMRV) does not cause chronic fatigue . Trends in Microbiology . November 2011 . 19 . 11 . 525–529 . 10.1016/j.tim.2011.08.005 . 21978843 . vanc.
  31. Alter . Harvey J. . Mikovits . Judy A. . Switzer . William M. . Ruscetti . Francis W. . Lo . Shyh-Ching . Klimas . Nancy . Komaroff . Anthony L. . Montoya . Jose G. . Bateman . Lucinda . Levine . Susan . Peterson . Daniel . Levin . Bruce . Hanson . Maureen R. . Genfi . Afia . Bhat . Meera . Zheng . HaoQiang . Wang . Richard . Li . Bingjie . Hung . Guo-Chiuan . Lee . Li Ling . Sameroff . Stephen . Heneine . Walid . Coffin . John . Hornig . Mady . Lipkin . W. Ian . 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 . November 2012 . 3 . 5 . e00266–12 . 10.1128/mBio.00266-12 . 22991430 . 3448165 . vanc.
  32. Sfanos . Karen S. . Aloia . Amanda L. . De Marzo . Angelo M. . Rein . Alan . XMRV and prostate cancer—a 'final' perspective . . February 2012 . 9 . 2 . 111–118 . 10.1038/nrurol.2011.225 . 22231291 . 4029112 . vanc.
  33. Lo . SC . Pripuzova . N . Li . B . Komaroff . AL . Hung . GC . Wang . R . Alter . HJ . Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. . . 7 September 2010 . 107 . 36 . 15874–9 . 10.1073/pnas.1006901107 . 20798047 . 2936598 . 2010PNAS..10715874L . free .
  34. Schlaberg . R . Choe . DJ . Brown . KR . Thaker . HM . Singh . IR . XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors . . 22 September 2009 . 106 . 38 . 16351–16356 . 10.1073/pnas.0906922106 . 19805305 . 2739868 . 2009PNAS..10616351S . free .
  35. Lombardi . Vincent C. . Ruscetti . Francis W. . Das Gupta . Jaydip . Pfost . Max A. . Hagen . Kathryn S. . Peterson . Daniel L. . Ruscetti . Sandra K. . Bagni . Rachel K. . Petrow-Sadowski . Cari . Gold . Bert . Dean . Michael . Silverman . Robert H. . Mikovits . Judy A. . Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome . . 23 October 2009 . 326 . 5952 . 585–589 . 10.1126/science.1179052 . 19815723 . 2009Sci...326..585L . vanc. free .
  36. Web site: Cohen . Jon . UPDATED: In a Rare Move, Science Without Authors' Consent Retracts Paper That Tied Mouse Virus to Chronic Fatigue Syndrome . . 5 March 2023 . https://web.archive.org/web/20221116035635/https://www.science.org/content/article/updated-rare-move-science-without-authors-consent-retracts-paper-tied-mouse-virus . 16 November 2022 . 22 December 2011.
  37. News: Tsouderos. Trine. Trine Tsouderos. October 3, 2011. Manipulation alleged in paper linking virus, chronic fatigue syndrome. Chicago Tribune. 28 October 2022 . https://web.archive.org/web/20221028001010/https://www.chicagotribune.com/lifestyles/health/chi-chronic-fatigue-syndrome-paper-10032011-story.html.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Xenotropic murine leukemia virus–related virus".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.