Xmrv the bridgebuilder

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Gerwyn

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XMRV DOES NOT NEED TO ENTER THE BLOOD AT ALL TO SPREAD THROUGH THE BODY.IN FACT ENTERING THE BLOOD SLOWS IT DOWN.THE VIRUS IN THE PAPER IS A MLV

Nature Cell Biology 9, 310 - 315 (2007)
Published online: 11 February 2007 | doi:10.1038/ncb1544

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o Nathan M. Sherer
o Maik J. Lehmann
o Luisa F. Jimenez-Soto
o Christina Horensavitz
o Marc Pypaert
o Walther Mothes
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Retroviruses can establish filopodial bridges for efficient cell-to-cell transmission

Nathan M. Sherer1,3, Maik J. Lehmann1,4, Luisa F. Jimenez-Soto1,5, Christina Horensavitz2, Marc Pypaert2 & Walther Mothes1

Abstract

The spread of retroviruses between cells is estimated to be 23 orders of magnitude more efficient when cells can physically interact with each other1, 2. The underlying mechanism is largely unknown, but transfer is believed to occur through large-surface interfaces, called virological or infectious synapses3, 4, 5, 6. Here, we report the direct visualization of cell-to-cell transmission of retroviruses in living cells. Our results reveal a mechanism of virus transport from infected to non-infected cells, involving thin filopodial bridges. These filopodia originate from non-infected cells and interact, through their tips, with infected cells. A strong association of the viral envelope glycoprotein (Env) in an infected cell with the receptor molecules in a target cell generates a stable bridge. Viruses then move along the outer surface of the filopodial bridge toward the target cell. Our data suggest that retroviruses spread by exploiting an inherent ability of filopodia to transport ligands from cell to cell.
 

Rosemary

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Hi Gerwyn,

Are filopodial bridges different from lipid rafts ?

When murine leukemia virus (MuLV) Env proteins associate with lipid rafts does this transfer happen in the blood ?

Here is an example

Palmitoylation of the murine leukemia virus envelope protein is critical for lipid raft association and surface expression.
Li M, Yang C, Tong S, Weidmann A, Compans RW.

Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

To investigate the association of the murine leukemia virus (MuLV) Env protein with lipid rafts, we compared wild-type and palmitoylation-deficient mutant Env proteins by using extraction with the mild detergent Triton X-100 (TX-100) followed by a sucrose gradient flotation assay. We found that the wild-type MuLV Env protein was resistant to ice-cold TX-100 treatment and floated to the top of the gradients. In contrast, we observed that the palmitoylation-deficient mutant Env protein was mostly soluble when extracted by ice-cold TX-100 and stayed at the bottom of the gradients. Both the wild-type and mutant Env proteins were found to be soluble when treated with methyl-beta-cyclodextrin before extraction with ice-cold TX-100 or when treated with ice-cold octyl-beta-glucoside instead of TX-100. These results indicate that the MuLV Env protein is associated with lipid rafts and that palmitoylation of the Env protein is critical for lipid raft association. Although the palmitoylation-deficient Env mutant was synthesized at a level similar to that of the wild-type Env, it was found to be expressed at reduced levels on the cell surface. We observed syncytium formation activity with both the wild-type and mutant Env proteins, indicating that palmitoylation or raft association is not required for MuLV viral fusion activity.
PMID: 12414927 [PubMed - indexed for MEDLINE]



Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9871-5.
 

MEKoan

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Gerwyn,

You're unearthing some pretty scary stuff!

I'm beginning to think of you as the Stephen King of XMRV!

:D
 

jspotila

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XMRV DOES NOT NEED TO ENTER THE BLOOD AT ALL TO SPREAD THROUGH THE BODY.IN FACT ENTERING THE BLOOD SLOWS IT DOWN.THE VIRUS IN THE PAPER IS A MLV
I know I don't understand molecular biology beyond the basics, but I don't see how the description of filopodial bridges in the abstract equates to the conclusion Gerwyn draws here about XMRV. If cells infected with retroviruses connect to uninfected cells, and this facilitates transmission of the infection, wouldn't that occur between blood cells? Why would XMRV be slowed down by entering blood cells? And how does the paper support the conclusion that XMRV does not need to enter blood cells to spread throughout the body? Can someone help me connect the dots?
 
G

Gerwyn

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I know I don't understand molecular biology beyond the basics, but I don't see how the description of filopodial bridges in the abstract equates to the conclusion Gerwyn draws here about XMRV. If cells infected with retroviruses connect to uninfected cells, and this facilitates transmission of the infection, wouldn't that occur between blood cells? Why would XMRV be slowed down by entering blood cells? And how does the paper support the conclusion that XMRV does not need to enter blood cells to spread throughout the body? Can someone help me connect the dots?

Blood cells are not in contact with each other Jenny. The retrovirus spreads from the infected cell to an uninfected neighbouring cell by means of the filopodian bridges two and a half times faster than any other method without any need to enter the bloodstream.It is a well known method for retroviral transfer.It is sometimes called cell-cell transfer.

Hope this helps

best wishes Gerwyn


Nathan M. Sherer1 and Walther Mothes2
1 Department of Infectious Diseases, King’s College London School of Medicine, London Bridge, London, SE1 9RT, UK
2 Section of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA
Cells use a variety of intercellular structures, including
gap junctions and synapses, for cell–cell communication.
Here, we present recent advances in the understanding
of thin membrane bridges that function in
cell–cell signaling and intercellular transport. Cytonemes
or filopodial bridges connect neighboring cells
via mechanisms of adhesion, which enable ligand-receptor-
mediated transfer of surface-associated cargoes
from cell to cell. By contrast, tunneling nanotubes establish
tubular conduits between cells that provide for the
exchange of both cell-surface molecules and cytoplasmic
content. We propose models for the biogenesis
of both types of membrane bridges and describe how
viruses use these structures for the purpose of cell-tocell
spread.
Introduction
Life depends on the ability of cells to communicate with
 

natasa778

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OMG I just remembered a doctor saying that when microscope viewing blood cells of kids with autism they often appear to have 'odd hair-like outgrowths'... going to try find out more details (or actually remember who it was :ashamed: )
 

jspotila

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Blood cells are not in contact with each other Jenny. The retrovirus spreads from the infected cell to an uninfected neighbouring cell by means of the filopodian bridges two and a half times faster than any other method without any need to enter the bloodstream.It is a well known method for retroviral transfer.It is sometimes called cell-cell transfer.

Hope this helps

best wishes Gerwyn
Still confused. Cell-to-cell transfer is different from a virus spitting out its particles into the bloodstream, with the particles wandering around and infecting new cells, right? So I get that the retrovirus is not "in" the blood in the same way viral particles would be. But cell-to-cell transfer can occur within the bloodstream, can't it? For example, the article that natasa778 linked showed cell-to-cell infection with HIV in T-cells in plasma (spun out from whole blood). So when you say that XMRV does not need to enter the bloodstream, are you saying that it does not follow cell-to-cell transfer among lymphocytes in the bloodstream? Or that it is not spitting out particles into the bloodstream?
 

jspotila

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spotila have a look at pics I posted...
natasa778, I did look at the pictures and article you posted. I confess the pictures were confusing to me. I did find this video of HIV cell-to-cell transfer that's very interesting. I'm still struggling to understand what Gerwyn means by "XMRV does not need to enter the blood" because it appears to me that cell-to-cell transfer can occur between lymphocytes in the bloodstream. Maybe I'm missing something . . .
 
G

Gerwyn

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natasa778, I did look at the pictures and article you posted. I confess the pictures were confusing to me. I did find this video of HIV cell-to-cell transfer that's very interesting. I'm still struggling to understand what Gerwyn means by "XMRV does not need to enter the blood" because it appears to me that cell-to-cell transfer can occur between lymphocytes in the bloodstream. Maybe I'm missing something . . .

XMRV is a gamma retrovirus Jenny not a lentivirus like HIV.XMRV can enter the blood but with cell cell transfer it does not need to.When cells are in constant contact with one another then the spread of retroviruses is two and a half times greater than when they are not.The paper actually looks at transfer in epithelial tissue.The problem with dendritic transfer in the blood is because the titres are orders of magnitude lower with a gammaretrovirus than a lentivirus and the contact is not long enough.The other point is that HIV replicates in the blood and XMRV as a MLV does not.It is largely latent and has developed cellular transfer and lipid raft formation as methods to minimise exposure to the immune system

Amphotropic murine leukaemia virus envelope protein is associated with cholesterol-rich microdomains

Christiane Beer1,2 email, Lene Pedersen2 email and Manfred Wirth1 email

1 Molecular Biotechnology, German Research Centre for Biotechnology, GBF, Mascheroder Weg 1, D-38124 Braunschweig, Germany

2 Institute of Clinical Medicine and Department of Molecular Biology, University of Aarhus, Aarhus, Denmark

author email corresponding author email

Virology Journal 2005, 2:36doi:10.1186/1743-422X-2-36
Published: 19 April 2005
Abstract
Background

Cholesterol-rich microdomains like lipid rafts were recently identified as regions within the plasma membrane, which play an important role in the assembly and budding of different viruses, e.g., measles virus and human immunodeficiency virus. For these viruses association of newly synthesized viral proteins with lipid rafts has been shown.
Results

Here we provide evidence for the association of the envelope protein (Env) of the 4070A isolate of amphotropic murine leukaemia virus (A-MLV) with lipid rafts. Using density gradient centrifugation and immunocytochemical analyses, we show that Env co-localizes with cholesterol, ganglioside GM1 and caveolin-1 in these specific regions of the plasma membrane.
Conclusions

These results show that a large amount of A-MLV Env is associated with lipid rafts and suggest that cholesterol-rich microdomains are used as portals for the exit of A-MLV.
 

julius

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OMG I just remembered a doctor saying that when microscope viewing blood cells of kids with autism they often appear to have 'odd hair-like outgrowths'... going to try find out more details (or actually remember who it was :ashamed: )
Keep us up to date on what you find out about this one.
 

alex3619

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Hi Gerwyn

Which can potentially explain why blood tests are so difficult to do successfully.

bye
Alex

XMRV DOES NOT NEED TO ENTER THE BLOOD AT ALL TO SPREAD THROUGH THE BODY.IN FACT ENTERING THE BLOOD SLOWS IT DOWN.THE VIRUS IN THE PAPER IS A MLV

Nature Cell Biology 9, 310 - 315 (2007)
Published online: 11 February 2007 | doi:10.1038/ncb1544
 

alex3619

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Hi Gerwyn

I get that red blood cells aren't likely to build bridges - they are essentially preprogrammed dying cells, with limited life expenctancy and must be contstantly replaced. Do you know if this is true of immune cells in the blood? Some types of immune cells deliberately communicate with each other in close contact, but I have not followed up on any specific mechanisms. You state that the contact has to be constant, this might imply that transfer between immune cells might only occur in the lymph nodes, since in the blood these cells are frequently too active. Does anyone have any thoughts on this?

Bye
Alex


XMRV is a gamma retrovirus Jenny not a lentivirus like HIV.XMRV can enter the blood but with cell cell transfer it does not need to.When cells are in constant contact with one another then the spread of retroviruses is two and a half times greater than when they are not.The paper actually looks at transfer in epithelial tissue.The problem with dendritic transfer in the blood is because the titres are orders of magnitude lower with a gammaretrovirus than a lentivirus and the contact is not long enough.The other point is that HIV replicates in the blood and XMRV as a MLV does not.It is largely latent and has developed cellular transfer and lipid raft formation as methods to minimise exposure to the immune system
 

Rosemary

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Recent studies shed new light on the potential role of Cav-1* in limiting HIV pathogenesis ...[*Caveolin-1 (Cav-1), the scaffold protein of specific membrane lipid rafts called caveolae]

HIV infection upregulates Caveolin 1 (Cav-1) expression to restrict virus production

Caveolin-1 (Cav-1) is a major protein of a specific membrane lipid raft known as caveolae...these results suggest that HIV infection enhances the expression of Cav-1 which subsequently causes virus reduction suggesting that Cav-1 may contribute to persistent infection in macrophages ....

http://jvi.asm.org/cgi/content/abstract/JVI.00763-10v1

XMRV is a gamma retrovirus Jenny not a lentivirus like HIV.XMRV can enter the blood but with cell cell transfer it does not need to.When cells are in constant contact with one another then the spread of retroviruses is two and a half times greater than when they are not.The paper actually looks at transfer in epithelial tissue.The problem with dendritic transfer in the blood is because the titres are orders of magnitude lower with a gammaretrovirus than a lentivirus and the contact is not long enough.The other point is that HIV replicates in the blood and XMRV as a MLV does not.It is largely latent and has developed cellular transfer and lipid raft formation as methods to minimise exposure to the immune system

Amphotropic murine leukaemia virus envelope protein is associated with cholesterol-rich microdomains

Christiane Beer1,2 email, Lene Pedersen2 email and Manfred Wirth1 email

1 Molecular Biotechnology, German Research Centre for Biotechnology, GBF, Mascheroder Weg 1, D-38124 Braunschweig, Germany

2 Institute of Clinical Medicine and Department of Molecular Biology, University of Aarhus, Aarhus, Denmark

author email corresponding author email

Virology Journal 2005, 2:36doi:10.1186/1743-422X-2-36
Published: 19 April 2005
Abstract
Background

Cholesterol-rich microdomains like lipid rafts were recently identified as regions within the plasma membrane, which play an important role in the assembly and budding of different viruses, e.g., measles virus and human immunodeficiency virus. For these viruses association of newly synthesized viral proteins with lipid rafts has been shown.
Results

Here we provide evidence for the association of the envelope protein (Env) of the 4070A isolate of amphotropic murine leukaemia virus (A-MLV) with lipid rafts. Using density gradient centrifugation and immunocytochemical analyses, we show that Env co-localizes with cholesterol, ganglioside GM1 and caveolin-1 in these specific regions of the plasma membrane.
Conclusions

These results show that a large amount of A-MLV Env is associated with lipid rafts and suggest that cholesterol-rich microdomains are used as portals for the exit of A-MLV.