Retroviral infection requires immune escape virulence factor encrypted in envelope

[joyscobby]

wwwwwwwwww wwwwww

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[julius]

"..the researchers were able to show that the HTLV and XMRV retroviruses associated with human diseases were both endowed with an immunosuppressive domain in their envelope protein."

Wow! That's great.

I heard Prof. Klimas theorizing that with individuals already infected, maybe you could use antiretrovirals to get the XMRV under control, and then pump in a vaccine to get the immune system to finish the job. Any thoughts?

 

[Kati]

This is excellent news and since it is edited by Dr Coffin, they have his seal of approval!!! Yay!

 

[julius]

Kati, nice catch. I didn't notice Dr. Coffin at first. Also, it's published in the online early edition, which shows the Academy thought it was important. Like the WPI study in the early edition of science.

BTW, am I reading these results correctly. Does this prove that XMRV is pathogenic, in that it causes immune dysregulation? (needing replication of course)

 

[FernRhizome]

Here's the abstract! Interesting!!! The CFIDS doctors will love hearing about this! ~Fern

Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses
Graldine Schlecht-Loufa,b,1, Martial Renarda,1, Marianne Mangeneya,1, Claire Letzeltera, Aurlien Richauda, Bertrand Ducosa, Isabelle Bouallagaa, and Thierry Heidmanna,2
+ Author Affiliations

aUnit des Rtrovirus Endognes et lments 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; and
bFacult de Mdecine Paris-Sud, Universit Paris-Sud, 94276 Le Kremlin–Bictre cedex, France
Edited* by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved January 6, 2010 (received for review November 13, 2009)

↵1G.S.-L., M.R., and M.M. contributed equally to this work.

Abstract

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.

infectious retrovirus immunosuppression innate immunity adaptive immunity vaccination
Footnotes

2To whom correspondence should be addressed. E-mail: heidmann@igr.fr.
Author contributions: G.S.-L., M.R., M.M., and T.H. designed research; G.S.-L., M.R., M.M., C.L., A.R., B.D., and I.B. performed research; G.S.-L., M.R., M.M., and T.H. analyzed data; and G.S.-L., M.R., M.M., and T.H. wrote the paper.
↵*This Direct Submission article had a prearranged editor.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0913122107/DCSupplemental.

 

[FernRhizome]

Kati: I didn't see Dr. Coffin's name anywhere in relation to this abstract/paper? Where did you see it??? ~Fern

 

[Kati]

fern, it's on the 8th line of the abstgract that you posted- it reads Edited by John Coffin...

 

[George]

I love this study!

Here's the abstract! Interesting!!! The CFIDS doctors will love hearing about this! ~Fern

Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses
Graldine Schlecht-Loufa,b,1, Martial Renarda,1, Marianne Mangeneya,1, Claire Letzeltera, Aurlien Richauda, Bertrand Ducosa, Isabelle Bouallagaa, and Thierry Heidmanna,2
+ Author Affiliations

aUnit des Rtrovirus Endognes et lments 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; and
bFacult de Mdecine Paris-Sud, Universit Paris-Sud, 94276 Le KremlinBictre cedex, France
Edited* by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved January 6, 2010 (received for review November 13, 2009)

↵1G.S.-L., M.R., and M.M. contributed equally to this work.

Abstract

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.

infectious retrovirus immunosuppression innate immunity adaptive immunity vaccination
Footnotes

2To whom correspondence should be addressed. E-mail: heidmann@igr.fr.
Author contributions: G.S.-L., M.R., M.M., and T.H. designed research; G.S.-L., M.R., M.M., C.L., A.R., B.D., and I.B. performed research; G.S.-L., M.R., M.M., and T.H. analyzed data; and G.S.-L., M.R., M.M., and T.H. wrote the paper.
↵*This Direct Submission article had a prearranged editor.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0913122107/DCSupplemental.

If Dr. Coffin is on board then we got ourselves one of the best voices in our corner we could ever possible have. I'm doing the CFS dance (you know the one where you dance around the room in your head (grins))

 

[Kati]

I think the title of this thread is a little misleading- this was not about vaccination research but more on understanding how the envelope of the retrovirus works and attaches to the cells. It certainly look good for vaccination, but I think it's a bit early to call it "Early XMRV vaccine research"

My 2 cents.

 

[usedtobeperkytina]

This sounds very similar to the study in Virology Today (is that right? I don't remember the name. Sorry, CFs cognitive problems.) Just published and mentions three fold increase and three fold degrease in XMRV replication, I think.

Tina

 

[_Kim_]

I think the title of this thread is a little misleading- this was not about vaccination research but more on understanding how the envelope of the retrovirus works and attaches to the cells. It certainly look good for vaccination, but I think it's a bit early to call it "Early XMRV vaccine research"

My 2 cents.

Kati, I changed the title. Here is a link to the full text in the Library.

 

[Kati]

Kati, I changed the title. I will be posting the full text in the Library next.

Thanks Kim!!!

 

[acer2000]

Thats interesting. There are some bacteria that code for similar toxins to throw the immune system. (Some of which cause food poisioning, etc...) These illnesses can sometimes be dealt with by administering a vaccine to the toxin, which then allows the immune system to effectively get rid of the infection. I wonder if that would work with this virus?

 

[Hope123]

Thanks for the article and the summary, Joyscobby, and thanks for the full-text, Kim.

Asus389, the vaccines which target bacterial toxins that I am familiar with (e.g. tetanus, diptheria vaccines) are ones where it's not the bacteria directly that's the problem but rather the toxins they produce. It's also not about evasion of the immune system. RE: food poisoning, I know of no current vaccines. Staphyloccal food poisioning is the most common (e.g. leaving mayonaisse out too long), caused by a toxin, but usually cleared with only supportive treatment and no specific treatmentsI Similarly with E. Coli. f you know otherwise, please elaborate.

 

[acer2000]

Perhaps I misunderstood. I though those bacterial toxins were in part to throw the immune system. I could wel be wrong though...

 

[Trooper]

"They were able to introduce targeted point mutations into the envelope protein that could suppress its ability to inhibit the immune system..."

Very interesting... thanks for sharing this paper

 

[Abraxas]

There is more discussion regarding this paper in the the thread entitled - 'New study - prospects for the treatment of retroviral diseases' - see here: http://forums.aboutmecfs.org/showthread.php?3005-New-study-prospects-for-the-treatment-of-retroviral-diseases