Susceptibility of the human retrovirus XMRV to antiretroviral inhibitors

[jimm]

http://www.retrovirology.com/content/7/1/70

XMRV to antiretroviral inhibitors

Robert A Smith email, Geoffrey S Gottlieb email and A Dusty Miller email

Retrovirology 2010, 7:70doi:10.1186/1742-4690-7-70
Published: 31 August 2010
Abstract (provisional)

Background

XMRV (xenotropic murine leukemia virus-related virus) is the first known example of an exogenous gammaretrovirus that can infect humans. A limited number of reports suggest that XMRV is intrinsically resistant to many of the antiretroviral drugs used to treat HIV-1 infection, but is sensitive to a small subset of these inhibitors. In the present study, we used a novel marker transfer assay to directly compare the antiviral drug sensitivities of XMRV and HIV-1 under identical conditions in the same host cell type.
Results

We extend the findings of previous studies by showing that, in addition to AZT and tenofovir, XMRV and HIV-1 are equally sensitive to AZddA (3'-azido-2',3'-dideoxyadenosine), AZddG (3'-azido-2',3'-dideoxyguanosine) and adefovir. These results indicate that specific 3'-azido or acyclic nucleoside analog inhibitors of HIV-1 reverse transcriptase (RT) also block XMRV infection with comparable efficacy in vitro. Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors nevirapine and efavirenz and to inhibitors of HIV-1 protease. In addition, we show that the integrase inhibitors raltegravir and elvitegravir are active against XMRV, with EC50 values in the nanomolar range.
Conclusions

Our analysis demonstrates that XMRV exhibits a distinct pattern of nucleoside analog susceptibility that correlates with the structure of the pseudosugar moiety and that XMRV is sensitive to a broader range of antiretroviral drugs than has previously been reported. We suggest that the divergent drug sensitivity profiles of XMRV and HIV-1 are partially explained by specific amino acid differences in their respective protease, RT and integrase sequences. Our data provide a basis for choosing specific antiretroviral drugs for clinical studies in XMRV-infected patients.

 

[Daffodil]

many are saying they need to target the already-integrated virus because it integrates into sites that evoke inflammation....what about that? ARV's wont work on that. that probably explains why many are not responding to ARV's

 

[George]

***Susceptibility of the human retrovirus XMRV to antiretroviral inhibitors***

Here's a nice Tidbit, woof, woof.

http://www.retrovirology.com/

XMRV (xenotropic murine leukemia virus-related virus) is the first known example of an exogenous gammaretrovirus that can infect humans. A limited number of reports suggest that XMRV is intrinsically resistant to many of the antiretroviral drugs used to treat HIV-1 infection, but is sensitive to a small subset of these inhibitors.

In the present study, we used a novel marker transfer assay to directly compare the antiviral drug sensitivities of XMRV and HIV-1 under identical conditions in the same host cell type.

Results: We extend the findings of previous studies by showing that, in addition to AZT and tenofovir, XMRV and HIV-1 are equally sensitive to AZddA (3'-azido-2',3'-dideoxyadenosine), AZddG (3'-azido-2',3'-dideoxyguanosine) and adefovir. These results indicate that specific 3'-azido or acyclic nucleoside analog inhibitors of HIV-1 reverse transcriptase (RT) also block XMRV infection with comparable efficacy in vitro.

Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors nevirapine and efavirenz and to inhibitors of HIV-1 protease. In addition, we show that the integrase inhibitors raltegravir and elvitegravir are active against XMRV, with EC50 values in the nanomolar range.

Conclusions: Our analysis demonstrates that XMRV exhibits a distinct pattern of nucleoside analog susceptibility that correlates with the structure of the pseudosugar moiety and that XMRV is sensitive to a broader range of antiretroviral drugs than has previously been reported.

We suggest that the divergent drug sensitivity profiles of XMRV and HIV-1 are partially explained by specific amino acid differences in their respective protease, RT and integrase sequences. Our data provide a basis for choosing specific antiretroviral drugs for clinical studies in XMRV-infected patients.

Author: Robert SmithGeoffrey GottliebA Dusty Miller
Credits/Source: Retrovirology 2010, 7:70

 

[VillageLife]

good news.

Our data provide a basis for choosing specific antiretroviral drugs for clinical studies in XMRV-infected patients

Great!!!! yipeeeee!!!

Dusty Miller, who is he again ? im sure ive heard of him before ?

 

[SOC]

If only I were comfortable believing anything published in Retrovirology......

 

[julius]

YAY!!!

 

[Recovery Soon]

Anyone care to guess when we might realistically expect such clinical trials to begin?

 

[George]

If only I were comfortable believing anything published in Retrovirology......

Yeah, they will publish anything won't they. (big grins)

Fortunalty you can count on anything coming from Dusty Miller. He has a dog in this fight somewhere. I haven't been able to find out who he knows that has CFS but the guy shows up at every conference, CAA webinar's and others. He's all about treatment. This looks like a good bit of investigating showing the amino acid chains in XMRV that can be targeted.

I am concerned that this may not go deep enough if the range of MLV's is wider than first expected, which I'm not sure if I buy. Usally the simpelest answer is the right one, ya know. It looks like our illness will turn out to be caused by a retrovirus (big duh) and that the virus will act along the same lines of HIV only you don't die as quickly. Most likely they'll find that all the "viruses" that we pick up along the way will go away with treatment of the underlaying cause. The prevelance of cancer will probably be found to go down as well. Not that we ever had proper demographics in the first place. (sigh)

I think folks like Dr. Miller and WPI will get those anit retroviril trials going pretty quick, end of this year or start of next year. That should clear up any delima about wheither it causes the illness. And how much recovery we can expect. Personaly I'd kinda like my brain back, I miss it.

 

[Recovery Soon]

I think folks like Dr. Miller and WPI will get those anit retroviril trials going pretty quick, end of this year or start of next year. That should clear up any delima about wheither it causes the illness. And how much recovery we can expect. Personaly I'd kinda like my brain back, I miss it.

Amen. I sure hope you're right. How much recovery DO you expect- in %?

 

[SOC]

Yeah, they will publish anything won't they. (big grins)

Fortunalty you can count on anything coming from Dusty Miller. He has a dog in this fight somewhere.

I'm SO glad to hear that! This paper sounds very promising.

Good dog, George!

 

[Daffodil]

dr. mikovits said before the end of the year i think

 

[George]

Now I need to find somebody to merge this thread with the one that Jim put up this afternoon! Oh moderators. . . . . . . . . . .

 

[George]

Hey Jim didn't see your post and posted the same in the treatment section. What say we get the admin's to merge em? You posted first so we'll merge with you, sound good?

 

[Daffodil]

perhaps someone can comment. i have been hearing that the virus(es) might be causing problems by integrating into a site in the genome that causes inflammation and so wont be able to be targeted with these drugs. also, the env proteins on the surface of the infected cells might be causing the problems and they wont be able to be targeted either. wont they have to target the latently infected cells for us to improve?

 

[George]

Hey Daffodil
The scientist who are interested in "treatments" have just gotten started in looking at what drugs will be effective. First they will have to "know" the virus and then look at existing drugs that will work and build drugs to fill in the gaps. There's a good chance that our treatment will look a lot like the HIV treatment programs. You are correct that for a "quick" recovery stopping XMRV/HGRV from replicating in the cell's that are already infected is crucial. This has probably been posted else where but what the heck, here's the basic menu that will have to be filled in in the coming months/years.

Reverse Transcriptase Inhibitors - These come in Nucleoside and Non Nucleoside types and will keep the virus from untwisting the DNA and then re-twisting with the viral RNA integrated into the DNA. Here they are filling in the Nucleoside but not the non Nucleoside inhibitors. But that's a good start.

Protease Inhibitors - PIs inhibit protease, which is another protein involved in the Viral replication process. Nothing about PI's in this batch but I haven't read through all the methods and stuff, if they tested for PI's and they failed I'll report back here.

Fusion or Entry Inhibitors- these prevent the virus from binding to or entering human immune cells so this could be a BIGGY if it turns out that like Feline Leukema virus this is based in the Bone Marrow and B cells (think about the rixitamaub sp? trial and the B cell lymphomas) then this would keep the virus from continuing to get into the bone marrow and the B cells so, over time you would see a lessening of symptoms.

Integrase Inhibitors- which they have some success finding here, integrase inhibitors interfere with the integrase enzyme, which Retroviruses need to insert its genetic material into human cells.

So yeah, they have some good starts and at least know what parts they need to fill in. The more possible drugs the better the chances of getting trials quickly. Since these drugs have already proven safe for for the treatment of retroviral infection, getting a permit for a trial from the NIH will be a lot easier and faster!

We extend the findings of previous studies by showing that, in addition to AZT and
tenofovir, XMRV and HIV-1 are equally sensitive to AZddA (3-azido-2,3-
dideoxyadenosine), AZddG (3-azido-2,3-dideoxyguanosine) and adefovir. These
results indicate that specific 3-azido or acyclic nucleoside analog inhibitors of HIV-1
reverse transcriptase (RT) also block XMRV infection with comparable efficacy in vitro.
Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors
nevirapine and efavirenz and to inhibitors of HIV-1 protease. In addition, we show that
the integrase inhibitors raltegravir and elvitegravir are active against XMRV, with EC50
values in the nanomolar range.

There's hope for the future.

 

[Rrrr]

george, one more question?

the paper says, "Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors
nevirapine and efavirenz and to inhibitors of HIV-1 protease."

what does that mean does it mean taht non-nucleoside RT inhibitors do not work to stunt xmrv?

best,
rrrr

 

[George]

I think it just means that the existing HIV drugs in those area don't work on XMRV. They will have to break down the virus and then build inhibitors based on the virus nucleotide chains themselves. But at least this way they can get us started on say an RT or integrase inhibitors at first and fill in the blanks so to speak, later.

 

[leelaplay]

This was in today's nytimes

"Judy A. Mikovits, the senior author of the Science paper, said she hoped to organize clinical trials of anti-retrovirals by the end of the year, noting that they could lead to answers about whether a retrovirus causes the disease as well as to effective treatments."

and the pdf file is out now. I am interested in the authors. Does anyone know more about them?

Here are the authors:

Robert A Smith1*, Geoffrey S Gottlieb2, A Dusty Miller1,3

1Department of Pathology, University of Washington, Seattle WA, USA
2Department of Medicine, University of Washington, Seattle WA, USA
3Human Biology Division, Fred... Hutchinson Cancer Research Center, Seattle WA, USA

 

[Rrrr]

I think it just means that the existing HIV drugs in those area don't work on XMRV. They will have to break down the virus and then build inhibitors based on the virus nucleotide chains themselves. But at least this way they can get us started on say an RT or integrase inhibitors at first and fill in the blanks so to speak, later.

thanks, george. however, it is all greek to me. i think i need to go learn about retroviruses and how they work and how antiretroviral meds work. i remember a while back someone posted a youtube video on it. i guess that is what i'll go look for!

FOUND IT! HERE IT IS
http://www.youtube.com/watch?v=eS1GODinO8w

 

[WestOzGirl]

I know it seems obvious to be focussing on antiretrovirals, as we are dealing with a retrovirus, but what about the B-cell depleting drug Rituximab? It has shown early promise is reversing CFS symptoms.