Eradicating HMRV (or whatever they name it next)

[Daffodil]

m0joey....i think coffin's opinion might be more reliable here, since the other doctor has a lot to gain from saying his product may be able to eradicate the virus.

i wish that somehow the recombinase drug for HIV would work....i think that might be our best hope. because our virus probably spends much of its time latent in bone marrow, it will be hard...

what they need is a really good delivery system for the recombinase. nanotechnology would provide this but seems to be in early stages..http://www.nature.com/nnano/journal/v5/n1/abs/nnano.2009.341.html

http://www.in-pharmatechnologist.co...-delivery-tech-lands-potential-1bn-Roche-deal

 

[mojoey]

Abstract: P_10
Therapeutics/ Vaccine (animal models)
Therapeutic targeting of TSG101 in XMRV-infected cells
J. Cassella1, M. Kohli1, M. Kinch1, L. Diaz1
1Functional Genetics Inc., Research and Development, Gaithersburg, USA

Work in our laboratory has demonstrated a promising opportunity for therapeutic or prophylactic intervention to combat infections by XMRV. Our approaches take advantage of the well-established fact that viruses “hijack” their hosts and alter the expression or function of particular host proteins to facilitate their propagation. Our studies have focused on one particular molecule, TSG101, which is a ubiquitously-expressed cytoplasmic protein that is known be “hijacked” upon viral infection. This hijacking of TSG101 is absolutely essential for budding of enveloped viruses. Moreover, targeted inhibition of TSG101 completely blocks propagation of viral infection, suggesting that the virus does not have secondary means for budding and maturation. Moreover, the utilization of host TSG101 is shared by many different virus families and all members within a given virus family.

For example, TSG101 is essential for infections caused by all retroviruses tested to date. Our laboratory has demonstrated that TSG101 is uniquely exposed on the surface of virus-infected cells and that this altered function provides much-needed opportunities for therapeutic targeting of retrovirus-infected cells. Specifically, TSG101 can be targeted using small molecules that prevent viral hijacking or using monoclonal antibodies, which serve to eliminate infected cells via normal host defense mechanisms. We will present promising preliminary evidence demonstrating that XMRV infection in particular is associated with surface exposure of TSG101. Consistent with prior findings linking XMRV with prostate cancer, we also demonstrate these changes in TSG101 appear to be highly relevant to prostate cancer based on immunohistochemical analyses of patient-derived prostate tumor specimens. We also provide preliminary insight as to studies meant to demonstrate efficacy of TSG101-targeted approaches for the treatment or prevention of XMRV-associated diseases. Altogether, these findings suggest potential opportunities for TSG101-directed therapeutic in the treatment or prevention of XMRV-associated diseases.

 

[leela]

This is really good news! Thanks for sniffing it out, mojoey.
Two really promising aspects:
"Moreover, targeted inhibition of TSG101 completely blocks propagation of viral infection, suggesting that the virus does not have secondary means for budding and maturation. Moreover, the utilization of host TSG101 is shared by many different virus families and all members within a given virus family.

For example, TSG101 is essential for infections caused by all retroviruses tested to date. Our laboratory has demonstrated that TSG101 is uniquely exposed on the surface of virus-infected cells and that this altered function provides much-needed opportunities for therapeutic targeting of retrovirus-infected cells.

I haven't fully read (or understood) all these, but there are more people out there looking at this entirely hopeful approach:
http://www.cell.com/retrieve/pii/S0092867401005062
http://onlinelibrary.wiley.com/doi/10.1034/j.1600-0854.2000.010307.x/abstract
http://jcb.rupress.org/content/162/3/425.full

 

[leela]

ALso this excerpt, from a realy long incomprehensible paper focusing on the way HIV works:

HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein

Owen Pornillos 1 , Daniel S. Higginson 1 , Kirsten M. Stray 1 , Robert D. Fisher 1 , Jennifer E. Garrus 1 , Marielle Payne 1 , Gong-Ping He 2 , Hubert E. Wang 2 , Scott G. Morham 2 , and Wesley I. Sundquist 1
+ Author Affiliations
1Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84132
2Myriad Genetics, Salt Lake City, UT 84108
Address correspondence to Wesley I. Sundquist, Dept. of Biochemistry, University of Utah, 20 N, 1900 E, Rm. 211, Salt Lake City, UT 84132. Tel.: (801) 595-8203. Fax: (801) 581-7959. email: wes@biochem.utah.edu
Back to TopAbstract

The HIV-1 Gag protein recruits the cellular factor Tsg101 to facilitate the final stages of virus budding. A conserved P(S/T)AP tetrapeptide motif within Gag (the late domain) binds directly to the NH2-terminal ubiquitin E2 variant (UEV) domain of Tsg101. In the cell, Tsg101 is required for biogenesis of vesicles that bud into the lumen of late endosomal compartments called multivesicular bodies (MVBs). However, the mechanism by which Tsg101 is recruited from the cytoplasm onto the endosomal membrane has not been known. Now, we report that Tsg101 binds the COOH-terminal region of the endosomal protein hepatocyte growth factorregulated tyrosine kinase substrate (Hrs; residues 222777). This interaction is mediated, in part, by binding of the Tsg101 UEV domain to the Hrs 348PSAP351 motif. Importantly, Hrs222777 can recruit Tsg101 and rescue the budding of virus-like Gag particles that are missing native late domains. These observations indicate that Hrs normally functions to recruit Tsg101 to the endosomal membrane. HIV-1 Gag apparently mimics this Hrs activity, and thereby usurps Tsg101 and other components of the MVB vesicle fission machinery to facilitate viral budding.

 

[mojoey]

Monoclonal antibodies are being discussed on the general treatment thread as a treatment for long-term infections. Rituximab is such an antibody that targets CD-20 expressing B-cells. What would be the possible adverse consequences of a chimeric antibody that targets TSG101 expressing cells? Do any non-infected cells express this protein?

Must...contact...Fundamental Genetics Inc.

 

[Daffodil]

how did you find this!? great work

TSG101 inhibitors cannot touch cells that have latent infections, though, right?

 

[leela]

From WikiP

Rituximab destroys both normal and malignant B cells that have CD20 on their surfaces, and is therefore used to treat diseases which are characterized by having too many B cells, overactive B cells or dysfunctional B cells.

IS this what you are referring to when you speak of adverse effects, Mojoey?
Would it not be good (I have no science) to target the gag protein (if xmrv has one that acts similarly) that is usurping the TSG101 instead?
Or am I talking out my arse?

 

[mojoey]

Hey Leela,

The gag and env proteins are intracellular and involved in the assembly and release of the virions, therefore they are not expressed on the surface of the infected cell and cannot be targeted by monoclonal antibodies (which look for surface targets).

The mature virus does express env proteins, so a therapy targeting that would attack freely-roaming viruses and a therapy blocking receptor sites for the protein that might stop viral entry into our cells, but I don't think any env-protein targeting would affect the virions that are already in the cell.

The TSG101 sounds promising particularly because it is expressed on the surface of the infected cells and therefore latent reservoirs could be targeted too.

 

[leela]

Thanks Mojoey. Starting to get a clearer picture.
You're going to be a full-on retrovirologist before too long...

 

[mojoey]

If I'm wrong about this, some please please call me out on it

 

[Daffodil]

im not sure if anything is expressed on cells with completely latent virus in it.....can someone clarify?

 

[leela]

Our laboratory has demonstrated that TSG101 is uniquely exposed on the surface of virus-infected cells and that this altered function provides much-needed opportunities for therapeutic targeting of retrovirus-infected cells.

I read the above to mean that only virus-infected cells have the TSG101 expressed. As far as I understand, there is no such thing as "completely" latent; just cells infected with a virus, latent until they have the opportunity to replicate via some trigger/immune assault. But I get stuff wrong....

 

[mojoey]

How'd I miss this....

It has been said that FeLV is similar to MLV, and has been studied in cats for decades. One of the main treatments for it is vaccination, and apparently it is much more feasible for FeLV than for HIV, so would the analogue apply to MLVs?

Here is the section on vaccines from the slides http://regist2.virology-education.com/1XMRV/docs/07_Sparger.pdf

Currently in use:
Whole inactivated virus (WIV) with adjuvant
Recombinant nonglycosylated SU (p45) via
bacterial expression and adjuvanted
Adjuvanted inactivated mixed subunit preparation
from FeLV cell culture filtrate

Nonadjuvantedcanarypox-vectored live vaccine
(ALVAC) containing FeLVEnv and Gag proteins
Transdermal delivery via a needle-free injection
system
Delivery selected to avoid issue of injection-site
sarcomas in cats

DNA vaccines encoding FeLV Gag/Pol and Env
Adjuvanted with cytokine expression plasmids:
interferon-gamma
IL-12
IL-18

Vaccine efficacy : Decreased incidence of FeLV
infection over past 25 years
- Current WIV vaccines : 44 - 100%
- Recombinant SU p45 : 87%
- Subunit vaccine : 55 - 63%
- Canarypox vectored : 78 – 100% **
DNA vaccine adjuvanted with IL-12 and IL-18
Showed 80-100% efficacy

 

[Daffodil]

yes i think i heard a vaccine would be much easier for our virus.

leela...thats what i thought..that even latent virus-infected cells express the protein but i am not sure now. if the virus is completely transcriptionally silent, i dont think it expresses anything...???

 

[mojoey]

http://sphotos.ak.fbcdn.net/hphotos-ak-snc4/hs661.snc4/60094_155217874502755_100000436316743_363142_1045485_n.jpg

Xand Xmrv on facebook posted this from Dr. Ferran at CIMA. Interestingly he came straight out and said wiping out the reservoirs with rituximab and other chemotherapy should be a priority over taking ARV.

Xand Xmrv: "Ferran also talkes about Quimio (chemo) drugs instead of retrovirals for CFS treatment, given the demosntrated mitochondrial failure on us. I hope they can explain further."

 

[Daffodil]

jeez. wouldnt we have to take chemo every few years then? wont the reservoirs keep replenishing themselves through mitosos? i dunno....maybe i'm completely wrong..

 

[mojoey]

I'm not validating his opinion in any way; I just thought it was noteworthy that a CFS doctor actually published that! That just shows how far we've come in terms of understanding this virus in a short amount of time

 

[Daffodil]

yes.

maybe rituximab would speed up the recovery process. ARV's seem to take a long time

 

[leela]

I feel very uncomfortable with the idea of chemo drugs. I dunno what to think. Also, Daffodil, does a vaccine work if you already have an active infection?

 

[Daffodil]

no that kind of vaccine wouldnt help if you have been exposed already, i dont think.

i dont know what to make of the rituximab trials. they started them before XMRV was discovered in CFS...and the studies are in norway it looks like....do they want to decrease provirus in bone marrow? are we at major risk for bone marrow related cancers? are they just going ahead with the trials because they have already been planned and funded?

i mean..i am sure rituximab would help us for a while, but now that we know the pathogen, why bother with it? unless people are very sure ARV's wont work. i was thinking this myself but now i have had a turn of events.