Date Published: September 4, 2011
Publisher: Hindawi Publishing Corporation
Author(s): Jonas Blomberg, Ali Sheikholvaezin, Amal Elfaitouri, Fredrik Blomberg, Anna Sjösten, Johan Mattson Ulfstedt, Rüdiger Pipkorn, Clas Källander, Christina Öhrmalm, Göran Sperber.
Gammaretrovirus-like sequences occur in most vertebrate genomes. Murine Leukemia Virus (MLV) like retroviruses (MLLVs) are a subset, which may be pathogenic and spread cross-species. Retroviruses highly similar to MLLVs (xenotropic murine retrovirus related virus (XMRV) and Human Mouse retrovirus-like RetroViruses (HMRVs)) reported from patients suffering from prostate cancer (PC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) raise the possibility that also humans have been infected. Structurally intact, potentially infectious MLLVs occur in the genomes of some mammals, especially mouse. Mouse MLLVs contain three major groups. One, MERV G3, contained MLVs and XMRV/HMRV. Its presence in mouse DNA, and the abundance of xenotropic MLVs in biologicals, is a source of false positivity. Theoretically, XMRV/HMRV could be one of several MLLV transspecies infections. MLLV pathobiology and diversity indicate optimal strategies for investigating XMRV/HMRV in humans and raise ethical concerns. The alternatives that XMRV/HMRV may give a hard-to-detect “stealth” infection, or that XMRV/HMRV never reached humans, have to be considered.
Recent reports of human gammaretroviruses highly similar to murine gammaretroviruses in PC and ME/CFS patients raise questions regarding (i) the occurrence of such retroviral sequences in murine and other vertebrate genomes, (ii) probable routes of spread of such viruses, and (iii) available methods for the detection of infection with them. In this review, we apply a phylogenetic aspect to the occurrence of XMRV/HMRV in genomes, and to the diagnostic search for it in humans. The comparative approach  can also enhance the study of pathobiology and epidemiology of XMRV/HMRV. Given the recent great activity in the field, the review cannot be exhaustive. Indeed, reports indicating that all XMRV/HMRV findings in humans may be due to different forms of laboratory contamination [2, 3] stress the need for a critical evaluation.
Gammaretroviruses related to the MLV were found 2006 in a few percent of patients suffering from prostate cancer . They were initially named XMRV. In 2009, XMRV was also found in patients suffering from ME/CFS . In 2010, the term XMRV was replaced with HMRV, because gammaretroviral sequences found in ME/CFS were found to be more diverse than just XMRV .
Research on XMRV/HMRV in humans is evolving rapidly. There is a great need for confirmation of the reports on XMRV/HMRVs in PC and ME/CFS. In view of the recently demonstrated diversity of retroviral sequences in ME/CFS, it is also important to establish the detection range of XMRV/HMRV detection methods. Contamination of cell cultures with 22Rv1 virus and PCRs with MLV nucleic acid and mouse DNA is known to occur. Whether all reports on MLLVs in humans can be explained by them is uncertain, but not unlikely. The XMRV/HMRV story has both credible and less credible aspects (Table 1). The original XMRV detection in prostate cancer was serendipitous and made with several independent techniques, together forming a credible case. The proven integration into human DNA was especially convincing. The finding of XMRV/HMRV in ME/CFS also has a credible aspect; the immunomodulating properties of MLLVs could theoretically explain the disease. However, the epidemiology of XMRV/HMRV transmission still is unclear. The absence of an easily measurable immune response is also a memento.