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),