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

Scientific Consensus is Building Towards XMRV as Causal Agent of ME/CFS

I had the opportunity to speak with one of the researchers who attended the  Cleveland Clinic conference a short while back.  Since the landmark study appeared in Science last month, several groups have been in a race to replicate the findings of Dr. Judy Mikovits - preliminary results are beginning to come in, while other researchers are waiting for their virus samples to arrive.  There is now reasonable certainty that XMRV is the causal agent of CFS/ME, as opposed to probable grounds at the time of publication.  It is hoped that by the middle of next year XMRV will beyond a reasonable doubt be shown to be the causal agent of ME/CFS.

XMRV seems to follow Koch's postualtes, except for the first one: "The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy animals."  The third "The cultured microorganism should cause disease when introduced into a healthy organism", and fourth "The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specified causal agent." has yet to be shown.  However, the main criticism of Koch's postulates is that it does not account for asymptomatic infections.

It is worth noting that there was considerable attention paid to possible therapeutic agents for ME/CFS.  This is still very much of a gray area at this time - and it will be several months before it is known which existing HIV drugs will work against XMRV - only a couple Reverse Transcriptase inhibitors, and Raltegravir have shown early promising results.  This in itself has already led to a few doctors prescribing AZT off-label to ME/CFS patients outside of clinical trials, in addition to a handful of individuals purchasing the drug online from internet pharmacies - however AZT IS NOT a drug that should be taken without medical supervision under any circumstance.