Inhibition of XMRV by a weapon of mass deamination

20 April 2010

deaminationCtoUAll 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). apobec_virionThey 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

  • John

    Could enteroviruses have anything to do with it?

    Nora Chapman and Stephen Tracy at the University of Nebraska have shown persistance of enteroviral infection in the apparent absence of infectious particles, and enteroviruses and CFS have a long association due to the epidemic nature of some outbreaks, incubation period, etc.

    One of, if not the first known outbreak of CFS was documented by future U.S. Surgeon General Alexander Gilliam at the Los Angeles County Hospital in 1934, with Dr. Gilliam calling the illness either 'atypical' or 'abortive' poliomyelitis, I can't remember which, although both descriptors have been used at one time or another when describing outbreaks of CFS.

    I think I've also read that the LACH staff was innoculated with serum from polio survivors, is it possible that one of the individuals serum was taken from was infected with XMRV?

    Also there's something wrong with PWC's RNaseL system, which produces a truncated 37kda form not found in healthy controls.

    Goody goody goody, time for people to start putting all the pieces of the puzzle together!

    “How does a lytic enterovirus persist and cause chronic disease?” – Nora Chapman
    International Symposium on Viruses in CFS & Post-viral Fatigue
    A satellite meeting of the 6th International Conference on HHV-6 & 7 in Baltimore, Maryland, USA Day 4 – June 23, 2008 – Enterovirus Session
    http://www.scivee.tv/node/7031

    'Human Enteroviruses and Chronic Infectious Disease' written for (or at least (re)published in) ME/CFS charity Invest in ME's newsletter Journal of IiME.
    http://www.investinme.org/Documents/Journals/Jo… -p.23

  • http://www.virology.ws profvrr

    I think it would be very useful to conduct viral discovery on samples
    from CFS patients, to discover whether any other pathogens might be
    involved. The patient cohort should be extensive and well defined, and
    deep sequencing and microarray analyses should be used. It's the best
    way to go through all the possible pathogens and see which, singly or
    combinations, are involved.

  • vdt33

    Profvrr, refer to the research paper

    Identification of Differentially Expressed Viruses in American CFS Patients Probed with a Custom Mammalian Virus Microarray. Judy Mikovits, V. Lombardi, Y. Huang, D. Peterson and F. Ruscetti

    Also:

    http://aboutmecfs.org/Conf/IACFSME09WPI.aspx

    “They used the latest technology for identifying viruses – microarrays — which search for bits of RNA and DNA unique to a pathogen. If they find these unique sequences they’re confident that the actual pathogen is present. This particular microarray looked for evidence of all known mammalian viruses, and it held multiple aspects of every known mammalian virus.”

    “The average chronic fatigue syndrome patient on the day they were tested had between 30-50 viruses; the average healthy control patient had 3 or 4” Dr. Daniel Peterson, 2008 Swedish Conference.”

    “The herpes viruses were the most active, including HHV4 (Epstein-Barr) HHV7, cytomegalovirus (CMV), and HHV-6. Cytomegalovirus was the most active virus found. Human endogenous retroviruses and enteroviruses were also found. Dr. Mikovits said the levels of viral expression they found were ‘incredible’.”

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  • http://swingtradingx.multiply.com/journal Swing Trading

    Interesting post. I have mde a twitter post about this. Others no doubt will like it like I did.

  • CBS

    Interesting new insight into HIV immune dysfunction, not just suppression : http://news.yahoo.com/s/nm/20100422/hl_nm/us_hi

    Dysfunction has been s suspected in CFS for years (see Dr. Chia's work on TH1/TH2 imbalance and enteroviruses).

  • CBS

    Interesting new insight into HIV immune dysfunction, not just suppression : http://news.yahoo.com/s/nm/20100422/hl_nm/us_hi

    Dysfunction has been s suspected in CFS for years (see Dr. Chia's work on TH1/TH2 imbalance and enteroviruses).