The scientific method at work: xenotropic murine leukemia virus–related virus is neither a cause of chronic fatigue syndrome nor a threat to the blood supply

S ir Francis Bacon (1561-1626), the Lord Chancellor of England, was the first to provide a documented philosophical method for investigating a natural phenomenon. This method later became known as “the scientific method. ” Unlike many before him, he suggested that our understanding of the world should be based on data, rather than faith or dogma. Moreover, his method required that our understanding of the world be provisional, with the hope that our current understanding of natural phenomena would eventually be replaced by better science. The events that have transpired over the past 2 years regarding the clinical relevance of xenotropic murine leukemia virus–related virus (XMRV) have shown that the method of scientific investigation first described 400 years ago is very much alive and well today. The scientific method, as envisioned by Sir Francis Bacon, starts with observation. Urisman and colleagues first observed that XMRV is associated with human disease in 2006, finding that 40% of men with prostate cancer and a low activity variant of RNase L, an enzyme involved in the interferon-induced antiviral response, were infected with this virus. Subsequently in 2009 and 2010, two groups of investigators also described finding XMRV or related sequences of polytropic murine leukemia viruses (MLVs) in association with chronic fatigue syndrome (CFS), a disease characterized by severe fatigue and other related symptoms lasting more than 6 months. XMRV is currently understood to be a retrovirus, but is unrelated to other well-described retroviruses such as human immunodeficiency virus (HIV) and human T-cell lymphotropic virus (HTLV). XMRV specifically is a member of the family Retroviridae, subfamily Orthoretrovirinae, and genus Gammaretrovirus (see AABB XMRV Fact Sheet http://www.aabb.org/resources/bct/ eid/Pages/default.aspx). XMRV is the first gammaretrovirus to be found in humans, and data indicate that it originated in mice after the recombination of two murine proviruses. Virions are 80 to 100 nm in diameter, consisting of an envelope, nucleocapsid, and a nucleoid with a linear dimer of positive-sense, single-stranded RNA. From these initial observations, it was hypothesized that this virus could be causally related to both prostate cancer and CFS. Moreover, the finding of viral sequences in the blood of healthy controls in two studies led to the concern that this virus could be transfusion transmitted, and thus the national blood supply could be at risk. Specifically, on June 18, 2010, the AABB issued a bulletin to its membership from its Interorganizational Task Force on XMRV that patients diagnosed with CFS be discouraged from donating blood. Consequently, the American Red Cross and a number of other blood donor centers started to offer educational information about CFS and have requested voluntary deferral of donors who ever have had a medical diagnosis of this debilitating condition. While the risk of transmission of XMRV by blood products was unknown at the time of release of this bulletin, the recommendation of the AABB Interorganizational Task Force was reasonable based on the initial hypothesis that CFS could have an infectious origin. First, XMRV is a gammaretrovirus, a genus that contains known animal pathogens (see AABB XMRV Fact Sheet). As other retroviruses, such as HIV and HTLV, are transfusion transmitted, it was plausible that an emerging retrovirus, such as XMRV, could also be transmitted by blood. Second, studies indicated that XMRV was physically present in blood. A rhesus macaque model of XMRV previously demonstrated that the virus can infect lymphoid cells, several tissues, and organs even though circulation of free virus was minimal. Moreover, Lombardi and colleagues found XMRV infection in the lymphocytes of the CFS patients From the Department of Pathology, Johns Hopkins University, Baltimore, Maryland; and the Scientific Support Office, American Red Cross, Gaithersburg, Maryland. Address reprint requests to: Susan Stramer, Scientific Support Office, American Red Cross, 9315 Gaither Road, Gaithersburg, MD 20877; e-mail: stramers@usa.redcross. org. Received for publication November 28, 2011; accepted November 28, 2011. doi: 10.1111/j.1537-2995.2011. 03518.x TRANSFUSION 2012;52:222-225.