Xenotropic murine leukemia virus-related virus (XMRV) was discovered in the tissues of prostate cancer cells and in patients who suffer Chronic Fatigue Syndrome (CFS). The search for its potential role in these diseases has given it much attention in the scientific community and investigating its nature can only lead to significant gains for both the scientific community and the public. Here, I investigate XMVR's structure, composition, lifecycle, and impact and role in prostate cancer and CFS.
Xenotropic murine leukemia virus-related virus is a part of the Baltimore class 6. XMRV is a retrovirus, which characteristically has a plus sense, non-segmented ssRNA genome. XMRV's linear genome is composed of roughly 8,185 nucleotides (Urisman et al. 213). The genome is an α-dimer consisting of two monomers joined near the 5' ends (Tidona 1024). The region of the genome that is transcribed is flanked by two long terminal repeats, one on each end, which are characteristic of retroviruses (Klein 125). The LTR regions contain the promoter regions, and include sequences such as the CCAAT box and a TATAAAA box (Urisman et al. 214). In addition, the virus comes equipped with a 5' cap and poly tail flanking the transcribed region (Klein 125). XMRV viruses are spherical to pleomorphic in shape (Tidona 1024) and are enveloped. The envelope contains glycoprotein spikes that bind to cell receptors and allow the envelope to fuse with the plasma membrane of the cell (Tidona 1024).
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Most key transcription products of XMRV come from cleavage of polyproteins encoded in the RNA. The GAG-PRO-POL sequence is transcribed and translated into a GAG-PRO-POL polyprotein, and is later cleaved into matrix protein (MA), capsid protein (CA), and nucleocapsid protein (NC). The PRO sequence is transcribed and translated into the protease protein (PR), which is involved in breaking down cellular proteins. The POL sequence is transcribed, translated, and cleaved into reverse transcriptase and integrase proteins. The ENV sequence is also transcribed, translated, and cleaved into surface (SU) and transmembrane (TM) proteins, which are bound together by disulfide bonds. The SU protein is glycosylated and is involved in attachment to host cell receptors, while the TM protein is involved in membrane fusion (Tidona 1029).
XMRV is a unique retrovirus in regards to its tropism. It is a provirus in murine (mice) species, but is unable to infect mouse strains. XMRV, being endogenous in mice, consequently do not carry the glycoprotein receptor on the cell surface of mice cells. The lack of glycoprotein receptors may be due to the presence of endogenous XMRV in the murine genome. Consequently, XMRV cannot infect mice, but can infect other mammalian cells, including humans (Levy 242).
XMRV replication begins with entry though the binding of SU glycoproteins with receptor proteins on the target cell. The envelope fuses with the plasma membrane of the cell, and the capsid enters and is uncoated. After uncoating, the genome is copied into linear dsDNA using reverse transcriptase and is transported into the nucleus. The DNA is then randomly inserted into the target cell genome using integrase protein. After integration, the viral DNA is referred to as a provirus. The provirus is transcribed using RNA polymerase II, which is present in the cell and transcribes the transcribed region. The 5' cap and the poly A tail are also synthesized and attached to the mRNA before exiting the nucleus. After being transported out of the cell, and m RNA is translated into three polyproteins: Env, Gag-Pro-Pol, and Gag.
As described earlier, these polyproteins are cleaved into smaller proteins during maturation, including p10, TM, SU, MA, CA, NC, and PR proteins. Replication of proteins continues simultaneously with the copying of the provirus into plus sense RNA. Virion assembly starts at the plasma membrane, which is also where XMRV egresses from the host cell. After the capsids are assembled, RNA is packaged into the capsids. This done by dimerization of two copies of the viral plus sense genome at the 5' ends. Following dimerization, p10 proteins, which bind to specific sequences in the dimerized genome, can package the dimerized genome into the capsid. The viruses egress from the host cell by budding through the plasma membrane and acquiring an envelope covering from the plasma membrane (Tidona 1024).
XMRV can infect a wide range of hosts, and is thought to stimulate proliferation of cells causing tumors. Current research is attempting to identify a link between XMRV and chronic fatigue syndrome (CFS), as well as prostate cancer. If there is a link between XMRV and prostate cancer, then it is probable that XMRV may be the source of the cancer, much like how human papillomavirus is the source of cervical cancer. In previous studies, the role of an antiviral gene in humans, the RNASEL gene, was tested to see if a mutation in the gene was associated with the presence of viruses. In the study, XMRV was found in the cancerous tissues that had a homozygous RNASEL mutation. The results imply that XMRV infection may suppress the protein product of RNASEL (Silverman et al. 393).
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After the detection of XMRV in the prostate cells, subsequent studies were performed to confirm the association between XMRV and RNASEL mutations and to investigate how XMRV is transmitted to humans. There was a study that did find a link between XMRV and RNASEL mutations, while other studies did not find a link between RNASEL and XMRV. Some view the conflicting data as a difference between the parameters of the experiments. For example, in a study done at Columbia University, hundreds of prostate cancer specimens from many areas of New York were analyzed, while other studies used a much smaller population of cancerous cells. This could cause for variations of the presence of XMRV due to geographical reasons. Currently, the possible link between the XMRV and RNASEL mutations are still being investigated (Silverman et al. 393).
XMRV has also been associated with Chronic fatigue syndrome. After the XMRV genome was found in the tissues of prostate cancer, a similar sequence was found in patients that were diagnosed with Chronic Fatigue syndrome (CFS). The virus in CFS patients was so similar that it was thought to be XMRV. To test if the virus was XMRV, studies were made to see if XMRV was found in prostate cancer tissues of patients with CSF. Like the studies of the RNALASE link to XMRV, the data showed conflicting results, with some patients having XMRV, and other patients lacking XMRV. Interestingly, the lack of XMRV in CSF tissues in studies performed in the US also suggests a geographic restriction of the virus, much like the XMRV and RNALASE linkage (Silverman et al. 396).
If XMRV is confirmed to be the cause of CFS and prostate cancer, then its effects are numerous. In CFS, the virus would most likely cause the autonomic dysfunctions seen in CFS patients. Symptoms include pain, drug intolerance, hyperalgesia, increased or decreased heart rates, bowel and bladder issues, and of course fatigue. Prostate cancer is marked by the proliferation, or abnormal increase in number cells in the prostate gland, resulting in tumor formation. Prostate cancer is often fatal, while CFS may take 1 or more years to recover from. There is a wide array of treatments for prostate cancer, including surgery, medications, radiation therapy, and hormonal therapy. CFS does not have a cure; often the symptoms are treated with antiviral medication, pain relievers, and antianxiety drugs. Prevention of prostate cancer is unknown, although have a balanced diet may lower the risk, along with early detection by regular screening. There are no preventative measures for CFS (Ugen et al. 377).
In conclusion, XMRV is a new retrovirus that is able to affect humans and other mammalian species. Its links to prostate cancer and CFS are still under investigation. Data on the links between XMRV and prostate cancer are conflicting, with some studies detecting the virus in certain prostate cancer tissues, while others do not detect the virus. The same pattern is seen in CFS studies, and both are thought to have regional restrictions of virus infection. The virus is unique in that it's endogenous in the murine species, and yet does not infect mice. It is able to affect other mammalian species, most notably humans. Its replication is typical of retroviruses, but the link between how it was able to infect humans is still unknown. Much more investigation is needed to understand XMRV, and more information about its possible role in prostate cancer and CFS will have significant impact on how theses diseases are treated in the future.