Retrovirus XMRV Is Inhibited by Host Proteins and Anti-HIV Drugs AZT, Tenofovir, and Raltegravir
These graphs show the susceptibility of XMRV to anti- HIV-1 drug treatments. Viral infections were carried out in the presence of increasing concentrations of anti-HIV-1 drugs. The concentrations needed to inhibit viral replication of both HIV-1 and XMRV by 50% (IC50) were determined. AZT, TDF, and raltegravir inhibit XMRV and HIV-1 with similar potency.
A newly discovered retrovirus, XMRV, isolated from prostate cancer tissues for the first time in 2006, has recently been reported in patients with this cancer, as well as in patients with chronic fatigue syndrome (CFS). However, five subsequent studies could not validate these reports. Since XMRV was isolated from the T and B cells of CFS patients, Vinay Pathak and his colleagues in the HIV Drug Resistance Program sought to determine how XMRV was countering intracellular defense mechanisms that inhibit retroviral replication in human cells.
Studies of interactions between HIV-1 and human host proteins have revealed intracellular defense mechanisms that inhibit the replication of a variety of viruses. For example, the proteins APOBEC3G (A3G) and APOBEC3F (A3F) are members of a family of cytidine deaminases that potently inhibit the replication of HIV-1 in the absence of the virally encoded Vif protein, in part by inducing massive amounts of G-to-A mutations in the viral genome. A3G and A3F also inhibit murine leukemia virus, a virus closely related to XMRV, and these proteins are expressed in human peripheral mononuclear cells such as CD4+ T and B cells. The Pathak team showed that XMRV is also highly sensitive to inhibition by A3G and A3F, and therefore, this virus most likely does not efficiently replicate in the CD4+ T and B cells that express these inhibitory proteins. The study suggests that the virus may replicate in cells that do not express these proteins, and could have important implications for the in vivo cells targeted by XMRV for infection.
XMRV is related to a family of retroviruses called gammaretroviruses; viruses within this family infect a wide range of mammalian species and are associated with a variety of cancers and neurological or immunological diseases. In view of the potential of gammaretroviruses to infect human cells and cause disease, Pathak and his colleagues sought to identify drugs that could inhibit XMRV replication in humans. They developed a cell culture assay to identify drugs that inhibit XMRV replication, and tested the ability of eight anti-HIV-1 drugs, namely zidovudine [AZT], lamivudine [3TC], didanosine [ddI], stavudine [d4T], abacavir [ABC], tenofovir [TDF], raltegravir [RAL], and foscarnet, to inhibit XMRV replication.
These results, published in the Journal of Virology, showed that AZT, tenofovir, and raltegravir inhibited XMRV replication at concentrations that are similar to those that inhibit HIV-1 replication. In fact, XMRV was about 2.5-fold more sensitive to raltegravir than HIV-1. While inhibition of XMRV by AZT was previously reported, these studies showed for the first time that XMRV replication could be inhibited potently by tenofovir and raltegravir.
These studies suggest that if XMRV is indeed found to contribute to human illness, anti-HIV-1 drugs AZT, tenofovir, and raltegravir may be useful for treatment of XMRV infection. Importantly, it may be possible to devise combination antiviral therapy for treatment of XMRV infection using these inhibitors. Combination therapies with three or more drugs have been an effective tool for controlling HIV-1 replication and suppressing the emergence of drug resistant HIV-1 in patients. A similar strategy may prove efficacious against XMRV replication.Summary Posted: Thu, 04/01/2010
Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu WS, Pathak VK. Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J Virol. March 24, 2010 PubMed Link