Inhibition of XMRV by a weapon of mass deamination
Posted Apr 20 2010 12:00am
All mammalian genomes contain genes encoding Apobec proteins. Several members of this protein family (the name stands for apolipoprotein B mRNA editing complex) are induced by interferon and are intrinsic antiretroviral proteins. Apobec proteins inhibit the replication of XMRV, a new human retrovirus associated with prostate cancer and chronic fatigue syndrome.
During retroviral replication, Apobec proteins are packaged into newly synthesized retrovirus particles (illustrated). They exert their antiviral effect when Apobec-containing virions infect a new cell. As the viral reverse transcriptase begins to copy viral RNA into DNA, Apobec removes an amine group from cytosines in single stranded DNA, a process called deamination. The consequence of deamination is that cytosine is changed to uracil. Uracil-containing DNA may be attacked by uracil DNA glycosidase, which removes the base and makes the DNA susceptible to degradation. If deaminated DNA is copied to form a double-stranded molecule, the new Us pair with As. In other words, deamination leads to a G-to-A mutation in the viral DNA. The highly mutated DNA cannot encode viable viruses, and the infection is terminated. For this reason one retrovirologist has called Apobec a WMD – a weapon of mass deamination.
Apobec is lethal for retroviruses that incorporate the enzyme into their virions. Human immunodeficiency virus-1 counters this defense by producing the Vif protein, which binds to Apobec and promotes its degradation by cellular enzymes.
XMRV does not encode a Vif protein and should be susceptible to inhibition by Apobec proteins. To answer this question, XMRV virions were produced in cells in the presence of different Apobec proteins. The deaminases were incorporated into virions, where they resulted in G-to-A hypermutation and inhibition of viral infectivity.
Could the presence of Apobec determine which human tissues are infected with XMRV? The virus replicates very well in a prostate cancer cell line, LNCaP, which produces reduced levels of Apobec proteins. Whether Apobec could regulate XMRV replication in the prostate is not known because expression of the protein in normal or malignant prostate tissues has not been studied. A conundrum which requires further investigation concerns the isolation of XMRV from CD4+ T and B cells, which are known to synthesize Apobec proteins. How XMRV might evade Apobec inhibition in these cells remains unexplained.
Paprotka, T., Venkatachari, N., Chaipan, C., Burdick, R., Delviks-Frankenberry, K., Hu, W., & Pathak, V. (2010). Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs Journal of Virology DOI: 10.1128/JVI.00134-10
Groom, H., Yap, M., Galao, R., Neil, S., & Bishop, K. (2010). Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors Proceedings of the National Academy of Sciences, 107 (11), 5166-5171 DOI: 10.1073/pnas.0913650107