Sunday, December 6, 2009

Antiviral Study Shows Few Options



A new Study released by Sakuma et. Al this week, provides groundbreaking new information on therapies for XMRV.  The results are not good: 10 licensed HIV-1 anti-virals were tested - only 1 showed strong activity, and 1 showed weak activity.  Out of the RTI's, AZT, 3TC, Tenofovir, D4T, Efavirenz, and Nevirapine were tested - only AZT showed strong activity.  Previously I reported that 3TC and Emtricitabine showed activity against a closely related virus: 3TC has negligible activity against this beast, and Emtricitabine remains untested.  The mechanism for 3TC resistance is likely a Valine substitution at position 184, in place of a methionine.  Emtricitabine, Abacavir, Etravirine, and Zalcitabine remain untested.  Three protease inhibitors were tested: Ritonavir, Indinavir, and Saquinavir: Only Ritonavir demonstrated weak activity at high concentrations - something that was not unexpected.  One experimental integrase inhibitor was tested: the compound 118-D-24 which was ineffective, good news is that it is structurally distinct from Raltegravir, and 118-D-24 does not inhibit MLV integrase either.

A comparison of the sequences reveals some astonishing details: the XMRV Reverse-Transcriptase resistance mechanisms are astonishingly similar to HIV mutations: Valine at position 75 is substituted with Glutamine (d4t resistance), Lysine at position 103 substituted with Serine (Efavirenz resistance), A Valine at position 106 is substituted with Tyrosine (Nevirapine resistance), A Methionine at position 184 is substituted with Valine (3TC resistance).  A closer examination reveals another stunning detail - most other drugs targeting Reverse-transcriptase are not likely to work, as the mutations giving rise to their resistance in HIV are apparent in XMRV.  The only good news is that XMRV does not foster the critical 4 amino acid mutation giving rise the Multi-nucleoside analog resistance.  Raltegravir still holds promise, as XMRV integrase bears a close sequence homology to MLV integrase.

Certainly, it is not a good situation.  The toxicity of AZT leaves a lot to be desired - HIV have much more tolerable Reverse transcriptase inhibitors at their disposal.  The development of drugs effective against XMRV has to essentially start from scratch - determining X-ray structures of XMRV Reverse Transcriptase, Protease, and integrase, modeling candidate molecules, conducting clinical trials, and seeking FDA approval.  The sequence differences of XMRV reverse-transcriptase will provide incentive for HIV drug research - the differences are what also gives HIV-1 resistance to current therapies.  We are basically where we were in 1987 with HIV - with Didanose (ddl) being only the second HIV drug to follow 4 years later.

This study only reinforces the urgency of kicking XAND research into high gear - 18 years were lost due to what I call criminal negligence at the CDC, and I am not afraid to call it the worst medical fraud of all time - only the CDC and their research cronies would stand to benefit -- not the patients, not the drug companies, not HIV patients, and not the doctors.  If the findings of Defreitas had been properly handled, patients with neuroimmune disorders would have options, and HIV patients would have drugs to treat resistant HIV strains.


Sakuma, R., et al., Xenotropic murine leukemia virus-related virus is susceptible to AZT, Virology (2009), 
doi:10.1016/j.virol.2009.11.013

7 comments:

  1. Disipointing findings indeed. On the other hand one could argue that its good news that at least one drug is likely to work and that two others may have potential.

    As for the CDC negligence I would not be surprised if there will be legal actions taken at some point. /Patrick

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  2. Thanks for your more expert review of the implications of this study for those of us not versed in these details. You did an excellent job, for me at least, in identifying what the more specific findings of Sakuma, et al tell us about future treatment directions. I was initially relieved that at least AZT was found to have effect, then disappointed at how little effect it was shown to have: inhibiting but not killing in existing infected cells. I know from dealing with bacterial sequelae (Chlamydia pneumoniae- Cpn) of CFS that so-called "dormant" cryptic forms of intracellular parasitic organisms still can cause on-going damage. Cryptic Cpn, while not metabolizing, secretes highly inflammatory HSP60 as part of its protective mechanism. I imagine that a retrovirus infected host cell is not as functional as it should be even if the virus is inhibited from replicating. Your thoughts on this?

    Oh yeah, I also appreciated your calling the CDC behavior what it is, "criminal negligence." The setback to not only US research, but the impact on world research on CFS/ME is appalling.

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  3. Thank you, Dr. Luckett. And also thank you to the knowledgeable people who posted comments.

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  4. jim k or dr. luckett...is there any drug that can target a dormant pathogen?

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  5. Timothy, Thanks for your expert insight into this discussion. And, yes, it can't be said too often that the CDC has behaved criminally.

    michael

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  6. This sucks I am sooooo tired of this illness I could scream!!!!!!! No one even believes it is true so you sit ,lay around all the time and Pray for a good day,people at Church even has abondoned me why?????????

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  7. Is there any possibility that didanosine could be effective against XMRV? Like AZT, didanosine is reported to one of the wider spectrums of activity against retroviruses including Feline Leukemia Virus, Friend Leukemia Virus,Harvey Murine Sarcoma Virus,Murine Lukemia Virus and Symian T Lymphotrophic Virus.

    Thanks,

    Dan

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