XMRV and Human Disease Association: Questions and Answers
- Posted: October 8, 2009
- Updated: May 31, 2011
- XMRV is a virus that is closely related to viruses known to cause cancer and other diseases in laboratory mice. (Question 1)
- The association of XMRV with cancers and diseases in humans has now been proven to be due to contamination from laboratory experiments. (Question 5)
- Other viruses might play a role in prostate cancer since it is known that a variety of viruses contribute to the causation of about 15 percent of known human cancers (Question 6).
XMRV, or xenotropic murine leukemia virus–related virus, is a retrovirus that was first reported in 2006 as a potential cause of prostate cancer. It is closely related to murine leukemia viruses, which cause a wide variety of cancers as well as immunological and neurological diseases in mice. It is known that XMRV is not spread in the air like influenza virus.
2. What is a retrovirus?
A retrovirus is a type of virus that has RNA instead of DNA as its genetic material. In infected cells, the RNA undergoes a process known as reverse transcription, in which DNA copies of the RNA are made and then inserted permanently into the host cells' chromosomes (organized structures of DNA and protein that are located within a cell's nucleus). If the viral DNA is expressed inside a host cell, the resulting RNA and protein molecules can be used to generate new virus particles. When retroviruses infect germ cells (sperm or egg), heritable forms of the viruses can arise. Then the integrated viral DNA, or provirus, is passed from parent to offspring. However, there is no evidence suggesting that XMRV can infect human germ cells.
Retroviruses are found in a wide range of mammals, and they can contribute to the development of cancers, such as leukemia or lymphoma, as well as neurological diseases. HTLV-1, the first human retrovirus identified, causes adult T cell leukemia. The second human retrovirus, HTLV-2 has not been associated with any disease. A third, human immunodeficiency virus (HIV), also known as HTLV-3, causes AIDS.
3. Is there a link between XMRV and cancer or other diseases?
XMRV was originally reported in 2006 in tissue samples from men with prostate cancer and was mostly found in combination with a specific defect in a gene called RNASE L, which helps the body defend against viruses.
A 2009 study of more than 300 prostate tissue samples collected from American men reported XMRV in 27 percent of the tumor samples from men who had been diagnosed with prostate cancer and 6 percent of the noncancerous prostate samples in men who had been diagnosed with benign prostatic disease. In contrast, a research group in Germany found no association between XMRV and prostate tumors. The group analyzed 589 prostate tumor samples for the presence of the virus and tested blood samples from 146 prostate cancer patients for antibodies to the virus and found no evidence of the virus or of antibodies to the virus. Another German study, and an Irish study, likewise found no evidence of a link between XMRV and prostate cancer. These differences in findings highlighted the need for more research on this virus.
The virus was subsequently reported to infect people with chronic fatigue syndrome (CFS). A study looking at clusters of CFS cases in Nevada, Florida, and South Carolina reported XMRV in 67 percent of 101 people with CFS, but in less than four percent of 218 healthy people.
4. What steps did NCI and other researchers take to arrive at a better understanding of XMRV's possible role in disease causation?
NCI convened an international meeting of scientists in July 2009 to discuss potential public health implications of XMRV. During this meeting, evidence was presented that suggested a link between XMRV and CFS. This evidence pointed to an immediate need for development of rapid and accurate diagnostic tools and methods to identify and analyze XMRV. NCI's Frederick, Md., laboratories established a XMRV action plan with the responsibility for producing the necessary research tools in both quality and bulk; established reproducible diagnostic platforms; and made their tools, technologies and expertise available to researchers in the broader scientific community, with a goal of undertaking large-scale epidemiological studies.
NCI-produced tools were made available to outside researchers through the NIH AIDS Reagent Repository (see https://www.aidsreagent.org/Index.cfm). At the same time, independent studies were initiated within NCI to determine whether XMRV was in people who had been diagnosed with CFS or prostate cancer. If a link was found, the goal was to try to establish whether the virus played a role in either condition and, if so, to determine whether antiretroviral therapies that are effective against HIV would display broad-spectrum activity against XMRV as well. NCI was the first to show that in addition to the anti-HIV agent AZT (one of the first drugs used against HIV), tenofovir and raltegravir potently inhibited XMRV replication.
In contrast to previous findings, and in keeping with reports that subsequently emerged in the literature, two independent NCI studies failed to detect XMRV in humans. In other studies, it was observed that XMRV replication is severely inhibited in human white blood cells, making it doubtful that XMRV replicated efficiently in the blood cells of CFS patients as previously reported. Additional evidence was obtained showing that previous data was potentially confounded by the presence of contaminating mouse DNA, and/or by contamination with XMRV virus in the laboratory.
Recent studies from NCI and Tufts University laboratories have shown that XMRV originated by recombination between two mouse viruses when human prostate tumors were grown in mice in the mid 1990s as part of experiments to develop an animal model system of human prostate cancer. Because all XMRVs that have been isolated and genetically sequenced are extremely similar to the virus that arose in this original recombination event, they are most likely to be laboratory contaminants derived from this recombinant virus. Using highly-sensitive XMRV DNA detection techniques (similar to those that have become the gold standard for HIV), coupled with methods to detect mouse DNA, NCI researchers tested new, independently-collected serum samples from a small selection of patients reported to be infected in the original 2009 Science publication that hypothesized a connection between XMRV and CFS. This analysis indicated significant levels of mouse DNA contamination in several of these samples; however, there was no evidence that any of the people tested a second time had been infected with XMRV. In addition, a sample of the XMRV viruses reported in the 2009 article has been cultivated from patient samples and was analyzed at NCI. In contrast to the original findings, the new data suggest it is unlikely that these XMRVs were derived from infected patients. Instead, like the other XMRVs that have been sequenced, they appear to be laboratory contaminants.
The NCI study is being reported in the same issue of Science as another study of XMRV (Knox et al.) that finds a lack of association between the virus and CFS even in the same patients from a 2009 study.
While studies now cumulatively and convincingly exclude a role for XMRV in prostate cancer and CFS, they do not rule out the possibility that some other virus or viruses might play a role in either disease. It is known that a variety of viruses contribute to about 15 percent of known human cancers.
Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung H, Tepper CG, Hu W, Fivash Jr. MJ, Coffin, JM, and Pathak VK. Recombinant Origin of the Retrovirus XMRV. Science. Online May 31, 2011.
Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett Jr. J, Qiu X, Luk K, Schochetman G, Knox A, Kogelnik AM, and Levy JA. No Evidence of Murine-like Gammaretroviruses in CFS Patients Previously Identified as XMRV-infected. Science. Online May 31, 2011.
Shin CH, Bateman L, Schlaberg R, Bunker AM, Leonard CJ, Hughen RW, Light AR, Light KC and Singh IR. Absence of XMRV and other MLV-related viruses in patients with Chronic Fatigue Syndrome. J Virol. May 4, 2011. doi:10.1128/JVI.00693-11
Coffin JM and Stoye JP. A New Virus for Old Diseases? Science. 2009. 326:530-531.
Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N, Denner J, Miller K, Kurth R, and Bannert N. Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology. 2009. 6:92.
Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, and Mikovits JA. Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science. 2009. 326: 585-589.
Schlaberg R, Choeb DJ, Browna KR, Thakerb HM, and Singh IR. XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. PNAS 2009. 106: 16351–16356.
Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL. Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant. PLoS Pathogen. 2006 2:211-225.
Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H, Aepfelbacher M, Schlomm
T. Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. J
Clin Virol. 2008. 43:277-283.
D'Arcy F, Foley R, Perry A, Marignol L, Lawler M, Gaffney E, Watson R, Fitzpatrick J, and Lynch T. No evidence of XMRV in Irish prostate cancer patients with the R462Q mutation. European Urology Supplements. 2008. 7:271.
Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu W-S, and Pathak VK. Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J. Virol. 2010. 84: 5719-5729.
Chaipan, C, Dilley, KA, Paprotka, T, Delviks-Frankenberry, KA, Venkatachari, NJ, Hu, W-S, and Pathak, VK. Severe restriction of xenotropic murine leukemia virus-related virus replication and spread in cultured human peripheral blood mononuclear cells. J. Virol. 2011. 85: 4888-4897.
Aloia AL, Sfanos KS, Isaacs WB, Zheng Q, Maldarelli F, De Marzo AM, and Rein A. XMRV: A new virus in prostate cancer? Cancer Res. 2010. 70: 10028-10033.
Li M, Dimaio F, Zhou D, Gustchina A, Lubkowski J, Dauter Z, Baker D, Wlodawer A.
Crystal structure of XMRV protease differs from the structures of other retropepsins.
Nat. Struct. Mol. Biol. 2011. 18: 227-9.