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Anti-HIV Drugs Show Activity against XMRV Retrovirus Linked to Prostate Cancer and Chronic Fatigue Syndrome

The integrase inhibitor raltegravir (Isentress) and certain other antiretroviral drugs used to treat HIV are also active against xenotropic murine leukemia virus-related virus (XMRV), a distantly related retrovirus thought to play a role in prostate cancer and chronic fatigue syndrome, according to a study described in the April 1 2010? issue of the open-access journal PLoS One.

XMRV is is classified as a gammaretrovirus, belonging to the same broad family as HIV, but more closely related to a group of viruses that cause cancers such as leukemia. Identified in 2006, XMRV has been linked to prostate cancer, and last fall researchers reported in Science magazine that more than 60% of individuals with chronic fatigue syndrome carried XMRV in peripheral blood cells. XMRV was the subject of a plenary presentation and an oral abstract session at the recent 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010).

Researchers from the University of Utah and Emory University tested 45 compounds, including 28 drugs approved for human use, for activity against XMRV in a laboratory study. They found that 4 anti-HIV drugs -- raltegravir, tenofovir (Viread, also in the Truvada and Atripla coformulations), zidovudine (AZT; Retrovir), and the experimental integrase inhibitor L-000870812 -- also inhibited XMRV replication.

When used together, these agents exhibited synergistic effects, offering the potential for combination therapy to delay the emergence of drug resistance. However, the study authors noted, XMRV has limited genetic diversity compared with HIV, indicating less capacity to develop drug resistance mutations, and suggested that 2 drugs may be adequate; notably, they were unable to select for raltegravir-resistant XMRV after trying for several months.

"While it is not yet clear if any illnesses are directly caused by XMRV, our data indicates that XMRV infections might be prevented or treated with specific antiviral agents," they concluded. "In the presence of any evidence of causality of human disease, our findings should provide the basis for designing clinical trials to treat them."

Below is the text of a press release from Emory University that provides more details about the study and its findings.

Anti-HIV Drugs Inhibit Emerging Virus Linked to Prostate Cancer, Chronic Fatigue Syndrome

Four drugs used to treat HIV infection can inhibit a retrovirus recently linked to prostate cancer and chronic fatigue syndrome, researchers at Emory University/Atlanta Veterans Affairs Medical Center and the University of Utah have shown.

The results were published on April 1, 2010 by the journal PLoS One.

The findings suggest that if XMRV (xenotropic murine leukemia virus-related virus) is proven to be a cause for prostate cancer or chronic fatigue syndrome, those illnesses may be treatable with drugs already approved for treating HIV.

Discovered in 2006, XMRV has been detected in some prostate cancer patients' tumor biopsies by several investigators. However, its precise role in driving prostate cancer is unclear. A recent report (from the Whittemore Peterson Institute in Nevada) detected XMRV in a majority of chronic fatigue syndrome patients, but these results have not been confirmed by other laboratories.

"Not all studies that have looked for XMRV have been able to detect it in prostate cancers or in samples from chronic fatigue syndrome," says Ila Singh, MD, PhD, associate professor of pathology at the University of Utah School of Medicine. "We will need to see the results of clinical trials before these drugs can be used in a clinical setting."

Singh and Raymond Schinazi, PhD, DSc, professor of pediatrics and chemistry at Emory's Center for AIDS Research and the Atlanta VAMC, and colleagues teamed up to test 45 anti-HIV compounds, some of these discovered by Emory researchers, and other antiviral compounds against XMRV in cell culture.

The most potent drug against XMRV was raltegravir, produced by Merck and sold under the commercial name Isentress. The FDA initially approved raltegravir in 2007 only for persons whose HIV infection was resistant to other drugs, but in 2009 its approval was expanded to all HIV infected persons.

Raltegravir represents a new class of antiretroviral drugs because it inhibits the integrase enzyme, preventing the virus from invading a cell's DNA. Other drugs against HIV inhibit either the reverse transcriptase enzyme, which copies the virus' genetic information, or the protease enzyme, which carves up newly produced viral proteins so that viruses can be assembled. However, none of the protease inhibitors inhibited XMRV in culture.

Besides raltegravir, three other compounds -- another integrase inhibitor and AZT and tenofovir DF, two reverse transcriptase inhibitors -- also inhibit XMRV replication. This suggests that these drugs could be used together in combination therapy, a particularly effective tactic against HIV that helps prevent the emergence of drug-resistant forms of the virus.

"Our study showed that these drugs inhibited XMRV at lower concentrations when two of them were used together, suggesting that highly potent 'cocktail' therapies might inhibit the virus from replicating and spreading," Schinazi says. "This combination of therapies might also have the added benefit of delaying or even preventing the virus from mutating into forms that are drug-resistant."

Although both XMRV and HIV are retroviruses, there is little similarity between HIV and XMRV at the protein level. Scientists have been able to show that several retroviruses cause cancer in animals, but only a few retroviruses are known to infect humans: human T-lymphotropic viruses 1 and 2, HIV, and now XMRV. Singh and Schinazi are now investigating the development of resistance in XMRV to raltegravir and other drugs.

Singh led a recently published study that demonstrated the presence of XMRV in 27 percent of prostate cancers examined, with the virus more likely to be found in the most-aggressive tumors. XMRV may promote cancer by integrating into the host cell DNA and warping the cell's regulation of its own genes.

Research supported by: Emory Center for AIDS Research and the Department of Veterans Affairs.

Department of Pathology, University of Utah, Salt Lake City, UT; Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Veterans Affairs Medical Center, Decatur, GA.

4/13/10

Reference

IR Singh, JW Gorzynski, D Drobysheva, and others. Raltegravir Is a Potent Inhibitor of XMRV, a Virus Implicated in Prostate Cancer and Chronic Fatigue Syndrome. PLoS One 5(4):e9948 (Free full text). April 1, 2010.

Other Source

Q Eastman. HIV Drugs Inhibit Virus Linked To Prostate Cancer, Chronic Fatigue Syndrome. Emory University. Press release. April 7, 2010.