What is XMRV and should we be worried about it?

Recently there has been growing controversy surrounding the newly identified xenotropic murine leukemia virus–related virus (XMRV). XMRV is a retrovirus from the Gammaretrovirus genus of the Orthoretrovirinae subfamily, with its name derived from the high sequence similarity in its envelope gene to the xenotropic murine leukemia virus (MLV), an endogenous MLV that infects cells from nonmouse species including humans.1 Unrelated to the human immunodeficiency virus (HIV) or the human T‐lymphotropic virus (HTLV), XMRV is the first agent of its class to be identified in humans and is likely to have originated in mice. A possible association of XMRV with prostate cancer was first reported in 2006,2 followed by evidence published last year of its association with chronic fatigue syndrome (CFS).3 The detection of XMRV in the lymphoid tissues of healthy individuals raised the concern that XMRV may be potentially transmissible by blood transfusion.3 Although these initial reports provided compelling evidence that XMRV is the first known example of an exogenous human gammaretrovirus, numerous subsequent studies could not confirm the detection of XMRV in human tissues or the association with human diseases.4-6 The potential threat from XMRV to blood safety has caused significant concerns in the blood transfusion community even though the verdict is still out regarding whether XMRV is a true human pathogen. This issue of TRANSFUSION includes two timely commentaries from expert working groups on XMRV and an original research article showing the absence of the XMRV in HIV‐infected blood donors or individuals in Africa.7-9 Together, these commentaries provide much‐ needed information on what we currently do and perhaps, more importantly, do not know about XMRV.

The three most crucial questions about any pathogen of potential concern to blood safety are: Does the agent cause disease(s) in humans? Can this pathogen be transmitted through blood transfusion? How can we minimize the risk of transfusion‐transmitted infection? Answers to these questions can only become available from substantial epidemiologic as well as laboratory studies. At present, results from the reported studies on XMRV are inconsistent and confusing.

IS XMRV A GENUINE HUMAN PATHOGEN?

To date there is no conclusive evidence to confirm a causative relationship between XMRV and any human disease. The first step to determine a microbial agent's etiologic role for a disease is to establish an association of the infection with the disease in question. So far widely disparate conclusions have resulted from efforts to assess the prevalence of XMRV in humans including patients with CFS and prostate cancer and healthy individuals. Most of these studies rely on sensitive polymerase chain reaction assay (PCR)‐based methods. Several recent reports suggest that inadvertent contamination may be responsible for false‐positive findings of XMRV in some human samples.4, 10-13 This high level of skepticism is well justified due to previous experiences of laboratory artifacts resulting in alleged findings of new human retroviruses.14, 15

Retroviruses are an important group of pathogens in animals and humans that cause a variety of diseases including cancers and chronic inflammatory conditions. Four human retroviruses have been discovered since 1980s (HIV‐1 and ‐2, HTLV‐1 and ‐2). XMRV now joins a long list of retroviruses as putative human pathogens that include human mammary tumor virus (in breast cancer), multiple sclerosis–associated retrovirus and human endogenous retrovirus (in multiple sclerosis), and betaretrovirus (in bronchioloalveolar carcinoma). These viruses acquired the labeling of “human rumor viruses” as their link to human infection and disease remains unproven and controversial.

The methods for establishing human infection for retroviruses include electron microscopy, detection of viral antigens and antibodies, viral culture, detection of viral nucleic acid sequence by PCR, and the recently developed bioinformatics and genomics tools. The high level of sensitivity of the PCR‐based methods has significantly enhanced our ability to detect novel viral sequences in human tissues but can also cause contamination‐related false‐positive results. Any new claims of retroviral infection in humans require a substantial level of proof. For XMRV, even if the detection of viral RNA sequences or antibodies can be confirmed in patient specimens, successful culturing of viable XMRV from patient samples is still needed to establish human infection. Furthermore, an infection on its own does not prove disease causation. The current controversy about XMRV once again reminds us that extreme care is needed in determining the connection between a retrovirus and human disease.

CAN XMRV BE TRANSMITTED BY BLOOD?

If its role as a human pathogen can be eventually proven, then XMRV should be considered as an emerging virus. The risk of transfusion‐transmitted XMRV infection will depend on several viral biologic and epidemiologic factors including the prevalence of XMRV infection in the donor population, the length of the asymptomatic blood‐borne period, viral load in asymptomatic donors, and the immune status of transfusion recipients. Both commentaries in this issue of TRANSFUSION carefully review the available information on the potential risk from XMRV to transfusion recipients. The well‐documented examples of transmissibility through blood of other human retroviruses such as HIV and HTLV certainly raise the possibility that XMRV may also be transmitted by blood. The alleged detection of XMRV in human peripheral blood mononuclear cells and plasma makes this possibility plausible.3 This possibility is further supported by findings that XMRV can infect lymphoid cells and disseminate to other tissues in the rhesus macaque model.16 Although this circumstantial evidence is intriguing, there has not been any direct proof to date demonstrating transmission of XMRV through blood. In some instances, epidemiologic data can offer indirect evidence for a pathogen's transmissibility though blood by linking an increased incidence of a disease with a history of blood transfusion. For XMRV, there has been no published data linking CFS or prostate cancer with previous transfusions in patients.

It is critical to note that data on this important issue are limited; therefore, no firm conclusions should be drawn at this time. Resolution of this issue awaits better understanding of the biology of XMRV and results from additional epidemiologic studies designed to evaluate the association between putative diseases caused by XMRV and a history of transfusion.

WHAT SHOULD BE DONE TO SAFEGUARD THE US BLOOD SUPPLY AGAINST A POTENTIAL THREAT FROM XMRV?

While actively following and contributing to the evolving science of XMRV in humans, the blood transfusion community has been working collaboratively since the early warnings of a developing concern to develop policies and procedures against the potential threat from XMRV. Simmons and coworkers8 describe the mission and progress of the Department of Health and Human Services' Scientific Research Working Group (SRWG). The SRWG's agenda focuses on reviewing available information and facilitating the acquisition of new data on the biologic and epidemiologic characteristics of XMRV, especially in the context of blood safety. The initial progress on standardizing the various tests for detecting XMRV in blood samples is a critical first step to resolve the controversy of XMRV's prevalence in patients as well as healthy individuals.

Klein and colleagues7 provide a report from the AABB's Interorganizational Task Force on XMRV which is composed of representatives of blood collectors, government agencies, and a not‐for‐profit organization dedicated to CFS research and policy, supplemented with additional scientific consultants. The Task Force was charged with evaluating scientific information regarding XMRV's potential as a risk for blood transfusion and cellular therapy and advising AABB about informing the blood transfusion community and the general public regarding the risk of XMRV transmission through transfusion. This commentary details the position and actions to date of the AABB, providing background information on AABB's June 2010 recommendation that medically diagnosed CFS patients should be discouraged from donating blood.17

Valuable lessons have been offered from our experience confronting previous emerging infections including HIV, West Nile virus, human herpesvirus‐8, and GB viruses.18-22 An effective system to deal with emerging infections in the context of transfusion safety should include elements to assess the level of the risk, to define the need and urgency of risk reduction interventions, to develop and implement interventions, and to evaluate the efficacy of interventions (and make adjustments as necessary).23 Key to the success of such a system is the effective collaboration between all stakeholders to protect the integrity of blood supply. The collective response from the blood transfusion community to XMRV demonstrates how government agencies, professional organizations, scientists, and industry leaders can work together in a timely and effective fashion when faced with a challenging situation such as the one we are in. This collaborative effort fulfills our collective responsibility to the millions of patients who receive blood transfusions each year.

Both commentaries offer thoughtful discussions on what actions to take against this new potential threat to blood safety given the lack of clarity around XMRV. If a risk of transmission through blood can be established, the usual candidate risk reduction measures could include interventions in donor selection, donor testing, and postdonation product manipulation. Careful considerations were given by both groups of authors, using available information, on the ramifications of various potential interventions regarding reducing XMRV's potential risk. The recently implemented donor deferral criteria (based on a past diagnosis of CFS) is consistent with the precautionary principle in that an intervention was enacted without the specific information about its efficacy, under the condition that no significant harm is involved.

As we continue to accumulate information on XMRV, the details about the need for intervention as well as the benefits and downside risks of different interventions will become clearer. This situation reminds us that when fighting a potential threat such as XMRV, as a part of a comprehensive risk reduction approach, broad spectrum–based pathogen reduction technologies may offer unique value especially when pathogen‐specific information and risk reduction measures are not yet available. It is worthwhile to point out the likely added value of international collaborations on these endeavors. Mechanisms for global collaboration on research and surveillance in blood transfusion such as the REDS Program sponsored by the National Heart, Lung, and Blood Institute should help to expedite progress when confronting potential new threats to blood supply domestically and globally.

Both articles acknowledge that our understanding of XMRV is still evolving and there is currently insufficient information to determine whether or not XMRV and related viruses are a threat to blood safety. The AABB Interorganizational Task Force will continue to collaborate with the SRWG, the Centers for Disease Control and Prevention, and the Food and Drug Administration as well as other partners in the blood transfusion community. This collaborative effort will focus on data collection and information dissemination to ensure early recognition of potential threats as well as effective development and evaluation of risk reduction interventions. Such resultant interventions should be based on sound scientific information to serve the purpose of protecting the integrity of blood supply, which includes both blood safety and availability.

CONFLICT OF INTEREST

None.