XMRV Discovery and Prostate Cancer-Related Research

Figure 3

Timeline of XMRV research. Highlights of XMRV studies are shown, including many of the investigations discussed in this review. The mapping of HPC1 to RNASEL was reported in 2002 [14] which led to the discovery of XMRV in 2006 using virochip technology [4]. In 2007, the first infectious clone of was constructed by fusing two overlapping cDNA from prostate cancer patient VP62 [30]. In addition, XPR1 was identified as the receptor for XMRV and the first integration sites in humans were reported [30]. In 2008, additional integration sites were mapped using human prostate cancer tissues [35]. A very low prevalence of XMRV was reported in sporadic prostate cancer patients in Germany [36]. In 2009, XMRV was identified in the human prostate cancer cell line 22Rv1, which had been repeatedly implanted and grown in mice [33]. In addition, a report of XMRV in prostatic malignant epithelium that correlated with tumor aggressiveness appeared [31]. The same year, a study using multiple methods of detection, including PCR, a serology assay for Env and isolation of live virus, showed XMRV in blood of CFS-ME patients, with much lower rates in healthy controls [37]. Studies into XPR1 function and specificity were reported between 2008 and 2010 [34, 38–41], including a study showing that whereas most laboratory strains of mice were resistant to infections, wild mice were susceptible [39]. A study from Germany that used PCR and antibody detection found no evidence of XMRV in prostate cancer [42]. In 2010, the androgen stimulatory effect on XMRV transcription and replication was reported [32, 43]. Host restriction factors, such as APOBEC3G and tetherin, were found to be active against XMRV [44–48]. Antiretroviral drugs were screened and some found to potently inhibit XMRV replication in cell culture [48–50]. The Asian mouse, Mus pahari, was exploited for studies on in vivo infection [50]. MLV-related sequences were found to associate with CFS-ME [51]. Meanwhile, several other studies, based on PCR and serology, failed to detect XMRV in CFS-ME (e.g., [52]). Two studies confirmed XMRV infections of prostate cancer patients [53, 54] while other studies failed to detect XMRV in prostate cancer patients in the US [55, 56]. Several assays for the detection of XMRV, including a high-throughput automated assay for antibodies against XMRV proteins, were reported [57]. XMRV was reported at a prevalence of almost 10% in immunosuppressed patients with respiratory tract infections in Germany [58]. Papers were published on laboratory contamination with mouse DNA that confounded the search for XMRV in humans [56, 59–62]. In early 2011, a study on XMRV in a non-human primate model showed wide-spread, persistent infection, including the prostate [63]. The crystal structure of the XMRV protease was published [64]. Finally, stimulation of XMRV transcription by proinflammatory cytokines through an NF-κB element in the LTR appeared [65].