XMRV Discovery and Prostate Cancer-Related Research

Abstract

Xenotropic murine leukemia virus-related virus (XMRV) was first reported in 2006 in a study of human prostate cancer patients with genetic variants of the antiviral enzyme, RNase L. Subsequent investigations in North America, Europe, Asia, and Africa have either observed or failed to detect XMRV in patients (prostate cancer, chronic fatigue syndrome-myalgic encephalomyelitis (CFS-ME), and immunosuppressed with respiratory tract infections) or normal, healthy, control individuals. The principal confounding factors are the near ubiquitous presence of mouse-derived reagents, antibodies and cells, and often XMRV itself, in laboratories. XMRV infects and replicates well in many human cell lines, but especially in certain prostate cancer cell lines. XMRV also traffics to prostate in a nonhuman primate model of infection. Here, we will review the discovery of XMRV and then focus on prostate cancer-related research involving this intriguing virus.

Figure 1

XMRV discovery in prostate cancer study [4]. Human prostate cancer tissues were collected in the operating room at the Cleveland Clinic and used to isolate RNA at either the Cleveland Clinic or at UCSF. At UCSF, RNA was used to synthesize labeled cDNA, virochips were probed, RT-PCR was performed for gag sequences, and XMRV cDNAs were sequenced. The RNase L genotypes were determined at the Cleveland Clinic (also the site of the IHC and FISH experiments, not shown). A hybridization pattern typical of a γretrovirus was obtained almost exclusively from patients with the RNase L QQ genotype (red bands and VP codes for QQ patients). RNase L RQ and RR genotypes are shown in black VP codes.

Figure 2

XMRV structure and morphology. (a) Structure of xenotropic murine leukemia virus-related virus showing viral core proteins from the gag gene (matrix (MA), capsid (CA), (IN), and nucleocapsid (NC) and p12); from pol (protease (PR), reverse transcriptase (RT), and integrase (IN)) and the envelope proteins (surface subunit (SU) and transmembrane subunit (TM) from env). Viral particles contain a lipid bilayer envelope and two RNA genomes. (b) Transmission electron microscope image of XMRV (courtesy of Dr. John Hackett, Jr., Abbott Diagnostics, Abbott Park, IL).

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 [, –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 [–48]. Antiretroviral drugs were screened and some found to potently inhibit XMRV replication in cell culture [–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 [, –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].