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Keywords:

  • blood safty;
  • gammaretroviruses;
  • policy;
  • XMRV

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. XMRV and other mouse-derived gammaretroviruses
  5. XMRV, CFS and blood safety
  6. Public concern and public pressure
  7. Disclosures
  8. References

XMRV is a recently discovered virus, related to mouse endogenous leukemia viruses. It was originally discovered in tissue from human prostate tumours and has been reported to be associated with chronic fatigue syndrome (CFS). Accumulating data suggest that the virus itself is a laboratory artifact and that many, if not all of the reported associations may be due to contamination of samples and or reagents. However, the association of this (and similar) viruses with chronic disease has attracted a great deal of public attention, particularly from CFS patients. Additionally, it was hypothesized that the virus might offer a risk to blood safety, generating additional pressures. Current data and perspectives on the issue will be discussed.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. XMRV and other mouse-derived gammaretroviruses
  5. XMRV, CFS and blood safety
  6. Public concern and public pressure
  7. Disclosures
  8. References

Human retrovirus infections offer a serious threat to the safety of the blood supply, as illustrated by the devastating effects of the HIV/AIDS epidemic. Even HTLV, the first human pathogenic retrovirus to be identified, was known to be transfusion-transmissible and has been linked to the development of tropical spastic paraparesis in a small proportion of recipients of blood from HTLV-infected donors. Of particular note is the fact that HIV is derived from simian viruses and that its clinical effects upon humans seem to be significantly more severe than those seen in its natural hosts. In other words, when a retrovirus jumps species, it may have increased pathogenicity in the new host. As a consequence, recognition of any new or emerging retroviral infection among humans is a matter of some concern. In 2006, a gammaretrovirus was recognized in the tissue of a proportion of cases of human prostate cancer. The virus was named xenotropic murine leukaemia related-virus (XMRV) and was shown to be related to a large group of endogenous mouse retroviruses [1]. The observation was somewhat controversial, but was regarded as definitive [2]. However, XMRV did not really impact transfusion medicine until 2009, when it was reported to be present in 67% of patients with myalgic encephalitis/chronic fatigue syndrome (ME/CFS, CFS) and 3·7% of healthy controls [3]. An accompanying commentary specifically mentioned the possibility of transfusion transmission of XMRV [4]. Almost all subsequent studies were unable to confirm these observations, but nevertheless careful consideration has been given to the possibility of transfusion transmission of this newly recognized virus.

XMRV and other mouse-derived gammaretroviruses

  1. Top of page
  2. Abstract
  3. Introduction
  4. XMRV and other mouse-derived gammaretroviruses
  5. XMRV, CFS and blood safety
  6. Public concern and public pressure
  7. Disclosures
  8. References

In 2006, Urisman et al. reported on a new human retrovirus, found in association with prostate cancer. The virus, named xenotropic murine leukaemia virus-related virus (XMRV) was identified through the use of Virochip technology and was specifically associated with a homozygous mutation in the RNASEL gene, a component of the interferon response pathway [1]. Subsequent studies have generated results that differ with respect to the prevalence of virus in prostate cancer patients, its relationship to the RNASEL mutation and its cellular location. Additionally, although clearly closely related by sequence homology to murine leukaemia viruses (MLVs), the actual origin of XMRV and the ways in which it entered the human population were unexplained. In 2009, in a report in Science, Lombardi et al. reported that they had identified XMRV in samples from 68 of 101 patients with ME-CFS and also in 8 of 218 normal controls (3·7%). In that study, multiple methods were used and infectious virus was isolated from the blood cells of some of the patients [3]. The virus itself was phylogenetically linked to a group of endogenous simple retroviruses (gammaretroviruses) affecting mice and other mammals. Although these viruses usually remain latent and quiescent as integrated DNA sequences, in some circumstances, they can be expressed as infectious virus with the capability of causing malignancies as a result of occasional integration into sites that activate oncogenes.

Recently, the likely origin of XMRV has been determined. The virus sequence itself has not been detected in mice, but careful studies have shown that different nude mice do carry viruses with DNA segments identical to different parts of the XMRV genome. It was shown that XMRV arose by recombination of these two viruses during successive passage of a human prostate cancer cell line in the two different mouse strains. Thus, although XMRV is a complete and functional virus, it is an artifact that arose during laboratory studies [5]. It appears that XMRV is highly infectious to human cell lines and has become a widespread contaminant in numerous laboratories. Apparently, similar contamination by native polytropic MLVs may also occur, although the actual mechanisms of such contamination are less clear. Nevertheless, it takes only a very low level of exposure. These findings have led to a better understanding of the significance of XMRV and related viruses.

XMRV, CFS and blood safety

  1. Top of page
  2. Abstract
  3. Introduction
  4. XMRV and other mouse-derived gammaretroviruses
  5. XMRV, CFS and blood safety
  6. Public concern and public pressure
  7. Disclosures
  8. References

The possible association of XMRV with a severe chronic disease and the significant prevalence of apparent infection among healthy controls, along with the implication of transfusion transmissibility was of concern to the transfusion community, but at the same time, it offered considerable hope to CFS patients. For many, it was perceived as a breakthrough that would lead to understanding the causation of the disease, support diagnosis and perhaps even open avenues to treatment; it was also seen as a signal that the disease was of physical, rather than psychological origin, thus adding legitimacy. The relevance of this issue will be discussed below.

The original CFS paper in Science was followed by a number of additional reports indicating that the authors were unable to find evidence of XMRV infection among different populations of CFS patients or controls. This pattern has continued and as of August 2011, there were 11 such negative reports (see review of publications in http://www.aabb.org/resources/bct/eid/Documents/xmrvtable.pdf). However, one paper reported on a finding of 86·5% of CFS patients with detectable MLV (not XMRV) sequences and 6·8% among blood donor controls [6]. Some took this to be supportive of the Science paper, but others challenged that interpretation, pointing out that the viruses were different and that the study only detected DNA sequences.

Further studies examined methodologies in detail and clearly established that the observations of XMRV and of MLVs in human samples could largely be accounted for on the basis of sample or reagent contamination by mouse-derived nucleic acids [5,7–10]. The recognition of the origin of XMRV also implies that virally contaminated tissue cultures could also be a source of unexpected contamination. It has been argued that such contamination could not account for reports of antibodies to XMRV in patient samples, but most of the research methods used to generate such data are inherently nonspecific.

In the meantime, the question of management of blood safety remained open. Some blood systems chose to defer individuals with CFS (or a medical history of CFS), even though this would have little impact if 4–7% of asymptomatic donors were infected. However, it has been argued that such a policy benefits CFS patients, who may suffer adverse effects from donation and also recognizes that even in the absence of XMRV, CFS may have an infectious etiology [11].

Two working groups were established in the US to consider the issues relating to blood. AABB, the professional organization for transfusion medicine appointed a group to advise their members on the situation and to make recommendations. The initial report of the group has been published and it includes a recommendation to educate presenting donors about CFS and to ask them to self-defer if they have had a medical diagnosis of CFS [12]. The AABB has also published and frequently updates a fact sheet about XMRV (http://www.aabb.org/resources/bct/eid/Documents/xmrvfactsheet.pdf) and provides a digest of current scientific publications, as noted above.

The second working group was sponsored by the National Heart, Lung and Blood Institute of NIH and is known as the Scientific Working Group (SWG). Its primary charge is to deal with three questions: What is the prevalence of XMRV in the US blood donor population; if present, is the virus transmissible by transfusion; and if transmitted, does the virus cause disease in recipients. A preliminary report outlining the group and its functions has been published [13]. To date, the major concern of the SWG has been to perform a three-phase study to determine the properties and comparability of available research and screening tests for XMRV infections by construction and distribution of carefully designed panels to a variety of research laboratories and test kit manufacturers. The laboratories making the original positive observations are included as participants and also as a source of some of the samples for testing. The published report shows that all laboratories can detect samples spiked with known amounts of XMRV and exhibit similar levels of analytic sensitivity. A critical, phase III study will involve coded samples from CFS patients, previously found positive and validated negative samples. A similar study funded by another part of NIH and managed by Ian Lipkin is in preparation. It is anticipated that these studies will define the extent to which the laboratories produce repeatable data and are comparable with each other: further, they should establish whether or not XMRV is truly associated with CFS.

Public concern and public pressure

  1. Top of page
  2. Abstract
  3. Introduction
  4. XMRV and other mouse-derived gammaretroviruses
  5. XMRV, CFS and blood safety
  6. Public concern and public pressure
  7. Disclosures
  8. References

As noted above and elsewhere, public concern may have a significant impact on the priority that is assigned to a transfusion-transmissible infection [14]. This has certainly been the case with respect to XMRV. As might be anticipated, regulatory agencies, such as the US FDA have expressed concern: the FDA has been supportive of measures to discourage donations by CFS patients and have promoted public discussion of the issues, but have not, as yet developed any guidance. Interestingly, CFS patients themselves have pushed for regulations to ‘ban’ donations by CFS patients and the Federal CFS Advisory Committee (which provides advice to the Secretary of HHS) has passed a motion to this effect. It appears that CFS patients believe that such an action would legitimize their disease and potentially result in additional attention and funding. This has been more explicitly presented in a newspaper advertisement comparing XMRV to HIV and implying an impending crisis. However, such attitudes seem to have lessened as the significance of the earlier observations comes into question. While some might argue that the precautionary principle dictates a need for immediate action, the XMRV working groups have argued that there really are insufficient data to support the immediate implementation of any further interventions: appropriate studies are under way.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. XMRV and other mouse-derived gammaretroviruses
  5. XMRV, CFS and blood safety
  6. Public concern and public pressure
  7. Disclosures
  8. References