Posted August 15, 2011
Matthew S. Karafin, MD
On June 18, 2010, the AABB issued a bulletin from its Interorganizational Task Force on xenotropic murine leukemia virus-related virus (XMRV) to its membership that patients diagnosed with chronic fatigue syndrome (CFS), a disease characterized by fatigue and other related symptoms lasting more than six months, be discouraged from donating blood. Consequently, the American Red Cross and a number of other blood donor centers have now started to offer educational information about CFS and have requested voluntary deferral of donors who have this debilitating condition.1
The recommendation was based upon evidence that CFS may be caused by XMRV.1 XMRV is a retrovirus and is similar, but unrelated, to other well-known retroviruses such as human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus (HTLV). XMRV specifically is a member of the family Retroviridae, subfamily Orthoretrovirinae and genus Gammaretrovirus (see AABB XMRV Fact Sheet). XMRV is the first gammaretrovirus to be found in humans, and recent data indicate that it originated in mice following the recombination of two murine proviruses.2 Virions are 80-nm to 100-nm in diameter, consisting of an envelope, nucleocapsid, and a nucleoid with a linear dimer of positive-sense, single-stranded RNA.3
XMRV, and its possible association with human disease, was first described in 2006, when Urisman et al found that 10% of men with prostate cancer were also infected with this virus.4 Subsequently two groups of investigators described finding XMRV or related sequences of polytropic murine leukemia viruses (MLVs) in association with CFS.5,6 However, following the potential association of XMRV/MLV with prostate cancer and CFS, many independent studies have been unable to demonstrate a relationship between XMRV/MLV infection and human disease (see AABB XMRV Fact Sheet Table). One review found that XMRV has been detected in 0% to 27.5% of prostate cancer patients in eight of 12 studies.3 The two positive CFS studies found that XMRV/MLV sequences were present in up to 86.5% of CFS patients and up to 7% of healthy controls including blood donors.5,6 As of early 2011, seven studies have failed to reproduce these findings in CFS patients.1 More recently, additional studies have failed to demonstrate a relationship of XMRV/MLV to CFS, including two studies with negative findings that appear to be the most significant7,8 since many highly sensitive methods were used modeled after those described by Lombardi et al.5 These methods include various molecular, serologic, and culture procedures, as well as the enrollment of many of the same CFS patients whose samples were tested by Lombardi et al.5 The reason for the wide differences between study findings was originally attributed to differences in cohort selection, testing methods, or sample source, preparation, and storage.1,9,10 However, recent data indicate that laboratory and/or reagent contamination are the most likely causes for the results in the studies with positive findings.2,7,8
As already mentioned, one study demonstrated that XMRV originated as a recombination event that occurred during the serial passage of mouse xenografts involving two mouse proviruses. When aligned, these two proviruses are identical to the sequence of XMRV. Thus, the authors conclude that all XMRV positive findings are the result of contamination by this laboratory-derived virus.2 The mounting negative findings failing to associate XMRV/MLV with human disease, and now documentation of XMRV as a laboratory artifact, have prompted the editor of Science to call for a retraction of the Lombardi et al publication; the retraction will be attached to the October 23, 2009, publication of Lombardi et al.11 Thus, the scientific community is rapidly reaching consensus that XMRV/MLV is not a human pathogen (see Lancet commentary12). However, there are two studies that are pending, both funded by the National Institutes of Health (one sponsored by the National Heart, Lung, and Blood Institute’s [NHLBI] Scientific Working Group on XMRV9 and the other sponsored by the National Institute of Allergy and Infectious Diseases led by Ian Lipkin of Columbia University); these two studies will either close the chapter on XMRV/MLV or indicate that all negative findings to date are in error, the latter of which seems unlikely.
The actual risk of transmission of XMRV by blood products is currently unknown. Even if the virus was created as the result of a laboratory-related recombination, it is still a Gammaretrovirus, a genus containing known animal pathogens (see AABB XMRV Fact Sheet). As other retroviruses, such as HIV and HTLV, are transfusion transmitted (see Table 1 below), it is plausible that an emerging retrovirus, such as XMRV, could also be transmitted by blood. A rhesus macaque model of XMRV has previously demonstrated that the virus can infect lymphoid cells.13 Moreover, Lombardi et al found XMRV infection in the lymphocytes of the CFS patients studied.5 As lymphocytes are present in transfused cellular blood components, such as platelet products, packed red blood cells, and granulocytes, there is a theoretical risk that this virus could be transmitted by transfusion.
The blood banking community is charged with ensuring and improving the safety of the blood supply and organizations such as the US Food and Drug Administration, Centers for Disease Control and Prevention, the AABB, and the NHLBI are active in monitoring continuing threats.1,9,14 The US blood supply is the safest that it has ever been due to focused donor health screening and extensive infectious disease testing. Units of donor blood are currently tested for evidence of hepatitis B and hepatitis C infection as well as HIV-1/-2, HTLV-I/-II, West Nile virus, and Treponema pallidum infection. The presence of Trypanosoma cruzi, cytomegalovirus (CMV), and bacteria are also determined on a selective testing basis.15,16 While the jury is still out on XMRV as a threat to blood safety, emerging transfusion-transmitted agents are of particular interest to the blood bank community because actions and policies aimed at prevention, like the one mentioned above, are needed to protect the safety of both blood donors and transfused patients.
|Table 1. Current transfusion-transmission risk of various infections
(adapted from the Compendium of Transfusion Practice Guidelines15)
|Agent||Prevalence in allogeneic blood donors||Recipient Risk*|
|HIV||1 per 34,883||1 per 1,467,000|
|HCV||1 per 2,748||1 per 1,149,000|
|HBV||1 per 11,443||1 per 282,000|
|HTLV||I/II 1 per 40,938||1 per 4,364,000|
|Treponema pallidum||1 per 4,054||None reported since the 1960s|
|West Nile virus (WNV)**||1 per 16,000||1 per 4,570,000|
|Trypanosoma cruzi***||1 per 76,560||None reported|
|* The risk is estimated based on data from 2006–2008.|
** The estimates presented are from the mosquito-virus transmission season.
*** Subsequent to 2008, two platelet recipients were identified by lookback to have obtained T. cruzi from a single positive donor (confirmed by serology, PCR, and culture).16
References and Suggested Reading
- Klein HG, Dodd RY, Hollinger FB, et al. Xenotropic murine leukemia virus-related virus (XMRV) and blood transfusion: report of the AABB interorganizational XMRV task force. Transfusion. 2011;51:654–661.
- Paprotka T, Delviks-Frankenberry KA, Cingöz O, et al. Recombinant origin of the retrovirus XMRV [published online ahead of print May 2011]. Science. doi:10.1126/science.1205292.
- Silverman RH, Nguyen C, Weight CJ, and Klein EA. The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. Nat Rev Urol. 2010;7(7):392–402.
- Urisman A, Molinaro RJ, Fischer N, et al. Identification of a novel gammaretrovirus in prostate tumors in patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006;2(3):e25.
- Lombardi VC, Ruscetti FW, Das Gupta J, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009;326(5952):585–589.
- Lo SC, Pripuzova N, Li B, et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci USA. 2010;107(36):15874–15879.
- Shin CH, Bateman L, Schlaberg R, et al. Absence of XMRV and other MLV-related viruses in patients with chronic fatigue syndrome. J Virol. 2011;85(14):7195–7202. doi:10.1128/JVI.00693-11.
- Knox K, Carrigan D, Simmons G, et al. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science. 2011;333(6038):94–97. doi:10.1126/science.1204963.
- Simmons G, Glynn SA, Holmberg J, et al. The blood xenotropic murine leukemia virus-related virus scientific research working group: mission, progress and plans. Transfusion. 2011;51(3):643–653. doi:10.1111/j.1537-2995.2011.03063.x.
- Shan H. What is XMRV and should we be worried about it? Transfusion. 2011;51(3):450–453.
- Alberts B. Editorial expression of concern. [retraction of Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, et al. In: Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009;326(5952):585–589]. Science. 2011;333(6038):35. doi:10.1126/science.1208542.
- Van Kuppeveld FJ, Van der Meer JK. XMRV and CFS-the sad end of a story [published online ahead of print June 20, 2011]. Lancet. doi:10.1016/S0140-6736(11)60899-4.
- Onlamoon N, Das Gupta J, Sharma P, et al. Infection, viral dissemination, and antibody responses of rhesus macaques exposed to the human gammaretrovirus XMRV. J Virol. 2011; 85(9):4547–4557. doi:10.1128/JVI.02411-10.
- Stramer SL, Hollinger FB, Katz LM, et al. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion. 2009;49(suppl 2):1S–29S.
- Quraishy N, Bachowski G, Benjamin RJ, et al. A Compendium of Transfusion Practice Guidelines. Washington, DC: American National Red Cross; 2010. http://www.redcrossblood.org/hospitals. Accessed June 24, 2011.
- Kessler D, Grima KM, Hillyer CD. Chagas transmission identified through lookback. Transfusion. 2010;50(suppl 2):31A–32A.
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