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

Raltegravir is likely effective against XMRV

Raltegravir (Trade name Isentress), is a drug that inhibits retroviral integrases.  In the article Beck et. al "Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir", the author states in Proceedings of The National Academy of Science that "the activity profile of raltegravir on the replication or murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role."  Both parts of this statement are highly significant.

The inhibition of Murine Leukemia Virus Integrase, which is almost identical to XMRV integrase, is not that surprising after all.  The catalytic sites of retroviral sequences have a series of conserved residues which are essential for activity, meaning that this enzyme is probably the best therapeutic target for XMRV.  Integrase inhibitors alone could work very well as monotherapy, and Dr. Mikovits stated that HAART is probably not necessary.  Because XMRV is a slow replicating virus, the chances of the virus becoming refractory to inhibitors of retroviral integrase are slim, as compared to HIV.  The drug raltegravir has a much, much better safety profile than NNRT's, which inhibit reverse transcriptase - which have side effects such as lipodystrophy, and the possibility of liver damage.  The downside is: Isentress is very expensive, costing about $1100 a month, something insurers definitely will frown upon - which may lead to some of them requiring a trial course of an NNRT before covering an integrase inhibitor.

The second part, where raltegravir induced lupus in genetically succeptible mice also could have a very profound effect in treating autoimmune diseases in the future.   What is significant is that Lupus favors one arm of the immune system, while Rheumatoid Arthritis, Psoriasis, Ankylosing Spondylitis, Crohn's disease favor the opposite arm.  This is significant, in that XMRV could induce the translation of endogenous retroelements - of which there are over 7,000 on the human genome -which human cells do not have the machinery to transform them into proteins (no human promoter can activate them), leading to the expression of foreign proteins on the surface of human cells, which makes the immune system recognize these cells as foreign.  It also lends credibility to the fact that Fibromyalgia is often co-morbid with disorders such as Rheumatoid Arthritis.  It also lends credence that Lupus is the polar opposite of RA, AS, Psoriasis - leading me to theorize that an antiretroviral could bring about a clinical remission in AS, RA, PsA patients - the same groups that currently benefit from anti-TNF therapy, but could exacerbate lupus.  So Lupus might be a true autoimmune disease, while on the opposite side a viral mediated quasi-autoimmune state exists.

**It is also noted that Echinacea extracts have been reported to produce lupus flares.

G.B. Beck-Engeser, D. Eilat, T. Harrer, H.-M. Jack, M. Wabl (2009). Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir Proceedings of the National Academy of Sciences : 10.1073/pnas.0908074106

A Primer on XMRV

XMRV is a retrovirus - a virus that uses its RNA to copy its genetic material into host DNA. The best known retrovirus is HIV (Human Immunodeficiency virus) - the virus that causes AIDS. XMRV is only the third such retrovirus discovered to infect humans, after the discovery of HTLV. Like HIV, XMRV has 3 genes in common - gag, pol, and env. The gag gene encodes the capsid and matrix proteins, the pol gene encodes a single protein which is cleaved into three separate proteins by the viral protease - reverse transcriptase, viral protease, and integrase, and the env gene encodes the envelope glycoproteins. The XMRV also contains an androgen response element gene, which I will discuss a theoretical role in a future post. The XMRV genome is somewhat smaller than the HIV genome - 8161 base pairs as opposed to ~9500 base pairs in the HIV genome. Based on initial findings, it appears that XMRV infects the immune system in ways that are all too familiar in HIV. The envelope glycoproteins likely bind to some yet unknown immune system protein like HIV binds to the CD4 receptor, and co-receptor, possibly CD8, CD 16 or CD 56 on the surface of NK cells.