New prospects for treatment of retroviral disease

[Guest guest]

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.Unité des Rétrovirus Endogènes et Eléments Rétroïdes

des Eucaryotes Supérieurs, Centre National de la Recherche Scientifique,

Unité Mixte de Recherche 8122 Institut Gustave Roussy, 94805 Villejuif, and

Université 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

+ Comments from a scientists on another board (public CFS board):

> ----------------

>

> 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).

>

> ...... 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...... Actually, since the same sequence is conserved in HTLV as well,

> it is very very likely (I dunno, 97%?) that this whole thing happens in humans

> as well as mice.

>

> ........ 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.