New study - prospects for the treatment of retroviral diseases

natasa778

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Proc Natl Acad Sci U S A. 2010 Feb 8. [Epub ahead of print]

Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses.

Schlecht-Louf G, Renard M, Mangeney M, Letzelter C, Richaud A, Ducos B, Bouallaga I, Heidmann T. Unit des Rtrovirus Endognes et Elments Rtrodes des Eucaryotes Suprieurs, Centre National de la Recherche Scientifique, Unit Mixte de Recherche 8122 Institut Gustave Roussy, 94805 Villejuif, and Universit Paris-Sud, 91405 Orsay, France.

We previously delineated a highly conserved immunosuppressive (IS) domain within murine and primate retroviral envelope proteins (Envs). The envelope-mediated immunosuppression was manifested by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to allow these cells to escape, at least transiently, immune rejection. Using this approach, we identified key residues whose mutation specifically abolishes IS activity without affecting the "mechanical" fusogenic function of the entire envelope. Here, we genetically "switched off' the envelope-mediated immunosuppression of an infectious retrovirus, the Friend murine leukemia virus, while preserving mutant envelope infectivity both ex vivo and in vivo, thus allowing us to test the functional importance of envelope-mediated immunosuppression in retrovirus physiology. Remarkably, we show, in vivo, that the non-IS mutant virus displays the same propagation kinetics as its WT counterpart in irradiated immunocompromised mice but that it is rapidly and totally cleared from normal immunocompetent mice, which become fully protected against a challenge with the WT retrovirus. Using cell depletion strategies, we further establish that envelope-mediated immunosuppression enables the retrovirus to escape innate (natural killer cells) and adaptive (CD8 T cells) antiviral effectors. Finally, we show that inactivated mutant virions induce higher humoral and cellular responses than their WT counterparts. In conclusion, our work demonstrates the critical role of Env-induced immunosuppression for retrovirus propagation in vivo and identifies a unique definite target for antiretroviral therapies and vaccine strategies, also characterized in the human T-cell leukemia virus (HTLV) and xenotropic murine leukemia virus-related virus (XMRV) retroviruses, opening unprecedented prospects for the treatment of retroviral diseases. PMID: 20142478
 

Adam

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Long low whistle.

Took a long time to read this as I was trying to stay with science (what Is WT?):confused:. But it sounds impressive. It also says; real scientists - working to help sick people. It gives a lot of hope...I think. Thank you for this Natasha. I think this thread will go viral.:Sign Good one:

Give yourself a pat on the back:victory:
 

Abraxas

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Thanks Natasa, this looks very interesting. Anyone with a scientific background care to explain this in simple terms ? !! :rolleyes:
 

Adam

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Wild type. Thanks Natasha. Thought it would be something really technical with ludicrously long words, which was why they were using acronymn.

I'm with you Abraxas. Scientists on forum - please tell us this is as good as it sounds?:Sign Please:

Adam
 
G

Gerwyn

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i would love to know if the is sequence silences gene expression in the glutathione or the( tgf) Beta -1 pathway .in simple terms if you take a bit of the viral RNA away the virus can still reproduce but can,t inhibit the hosts immune system.So there is a base sequence that is responsible for combatting the hosts defences If a retrovirus is able to silence or stop the hosts immune system working properly by not being able to make certain proteins/enzymes then it creates a "snowball effect" damaging the mitochondria,inhibiting the hypothalamus etc ---In other words the symptom complex of ME------now XMRV has a unique base sequence in the env gene which could therefore be immunosuppressent .If it is shown to be so then it could be the key to understanding ME.What happens is that one part of the immune system is "Killed off" and the other bit becomes hyper stiulated causing horrible problems in the mechanism s that control "autonomatic" process in the body and damage the cells power houses that now cant provide the needed energy.
 
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OK, I've read much of it. This will be a crude once-over synopsis.

Basically, these people discovered that certain retroviruses including XMRV encode a piece of a molecule with a very potent immunosuppressive function. They made mutant viruses which lack this function, and those viruses basically could not infect mice.

To give a little more detail for those with some background, it seems the Env (envelope) protein of a group of retroviruses including XMRV is not just an envelope protein. It is within the Env that this group discovered this potent immunosuppressive domain which.

The weak mutant virus without the immunosupressive domain fails to infect normal mice. It does better when the mouse's NK and CD8 cells are hampered artificially. Therefore, the new immunosuppressive domain somehow puts a damper on these immune cell types doing their thing. Which is of course to kill varmints like retroviruses et al.

The weak mutant virus induced a much stronger immune response. Why Mister, lymphocytes were spewing much more IFNg and other fine molecules that would, when produced in sufficient quantities, kill stuff and resolve an infection.

So, if a drug can inhibit thise immunosuppressive molecule domain robustly, that alone might plausibly bring the immune system around, to the extent that it would suppress XMRV to non-pathogenic levels and you would feel fine. What's not clear, apparently, is what that little domain is and does. Therefore, it doesn't necessarily have to be druggable, but my half-informed guess is that the chances are probably pretty fair. Some types of interactions that *might* be occurring here, namely protein-protein interactions, can be relatively difficult to inhibit well with drugs -- but that doesn't necessarily mean it can't be done. Especially when there is a huge amount of potential revenue to be made, which means we might see very large and very flush research projects in several firms (almost all drug discovery is done by the private sector, which has a lot more dough than government entities like NIH).
 
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It seems actually to be possible though, that this new immunosuppressive domain does not act in humans the way it does in mice. If so it would not really be important to us humans. However, that does not appear likely.
 
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This also has big implications for preventive vaccines. When you give someone a vaccine you must always include an adjuvant that riles up the immune system. It would now seem that some retroviral vaccines have included an anti-adjuvant, namely the immunosuppresive Env domain. One can snip that thing out of there and perhaps get a much more effective vaccine.

And come to think of it, I don't see why a therapeutic version of such a vaccine might not work for this as well. That is to say, a vaccine for those of us who already have XMRV and are sick (assuming it is in fact the cause). It is at least a possibility, and might be able to do the job if the new domain can't be robustly inhibited with a drug. It might also be easier and faster to develop than a drug would be.
 

Abraxas

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Thankyou to Gerwyn and Eric for your explanations, that's helped to clarify the gist of the study for me (although the finer points are a bit beyond me, with having no background in science :rolleyes: )

Anyone else want to add to their thoughts or explanations to help get a bigger picture? :Retro smile:

It looks promising and would be great if it leads somewhere.

Also does anyone have access to the full study and is it possible to put it in the library?