Avid Bioservices Inc (CDMO)

[jazzbeerman]

"This substantial five-year contract award is especially timely in view of recent scientific publications highlighting the broad anti-viral potential of our anti-PS agents such as bavituximab," said Steven W. King, president and CEO of Peregrine.


'What's he referring to', you ask?........



The tide has turned in the past couple months, as science has recognized that PS is responsible for entry of viruses into cells, and also that PS tricks the immune sysytem into not putting up a fight.



In April, a paper was published in the journal Science, by Mercer and Helenius:

:Vaccinia Virus Uses Macropinocytosis and Apoptotic Mimicry to Enter Host Cells

Jason Mercer and Ari Helenius

http://www.ncbi.nlm.nih.gov/pubmed/18436786?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


It describes how PS is responsible for viral entry into cells.

It discusses how PS stops the immune system from mounting a fight.

It even has MOVIES of virus entering a cell, and the cell having eruptions of PS blebs on it's surface...




--------------------------------




In the same issue of Science, other authors discussed how important the Mercer/Helenius findings were:

They also speculated that HIV may use the identical method of infection, and that,

"The role of phosphatidylserine
in the entry of HIV and other
viruses will surely be explored in greater
detail now.
"


A One-Sided Signal

Gregory D. Fairn and Sergio Grinstein

Changes in the distribution of a lipid within the
plasma membrane affect normal cell function
and virus infection.

As reported by Mercer and Helenius, loss
of phosphatidylserine asymmetry in the
plasma membrane is also important for some
viral infections. Like other viruses with a
lipid bilayer coating, vaccinia virus acquires
its membrane envelope as it buds off of the
infected host cell. Because the infected cells
undergo apoptosis, and thus experience
scrambling of plasma membrane lipids, the
budding virus also acquires an envelope that
exposes phosphatidylserine on its external
surface (see the figure). The authors found
that, although not required for the virus to
bind to the surface of the host cell, the presence
of exofacial phosphatidylserine is
required for viral entry. The nature of
the internalization pathway is particularly
intriguing because like other poxviruses,
vaccinia virus is large (³200 nm in diameter),
exceeding the size accommodated by
endocytosis, the engulfment process that
uses specialized minute invaginations to
internalize only a small area of the cell surface.
Using a series of pharmacological
agents, the authors showed that vaccinia
enters cells by a process akin to macropinocytosis
a less specific internalization
process that is more generally involved in the
uptake of surrounding fluids. The sensitivity
of vaccinia entry into cells to inhibitors of
tyrosine kinases suggests the involvement
of a transmembrane receptor for phosphatidylserine,
as well as the existence of
separate binding determinants on the receptor
for the virus and for phosphatidylserine.
This is consistent with a “tether and tickle”
mechanism in which a separate attachment
site is required for phosphatidylserine receptors
to effectively bind and internalize apoptotic
cells (8). The involvement of phosphatidylserine
may not be limited to infection
by vaccinia viruses. Papuamide B, a natural
compound with anti-HIV properties,
also binds to phosphatidylserine (9). It is
therefore conceivable that HIV similarly
requires phosphatidylserine for infection and
that papuamide B interferes by occluding the
lipid on the viral surface. The role of phosphatidylserine
in the entry of HIV and other
viruses will surely be explored in greater
detail now.



---------------------------



Here is a beautiful illustration form the Fairn & Grinstein comments in Science.









-------------------------------




The Mercer/Helenius paper in Science spawned several articles about the work. The role of exposed PS was simply and beutifully described in layman's terms in the following articles:

Have a look at these hits, googling the title: "A Step Forward In Virology"
http://www.google.com/search?hl=en&q=%22+A+Step+Forward+In+Virology%22&btnG=Search

As for the article-
It's beautiful how the author simplified the process of apoptotic phagocytosis for the reader:

- (the fact that exposed PS is a sign of a dying host cell,
- and that exposed PS signals immune cells not to mount a fight etc.)

- by caling PS "cell waste",
and an "official waste tag"! :)

That's just brilliant IMO.
Well done.

This same article is also spreading under the title, "Trojan Horse Of Viruses Revealed"
http://www.google.com/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&q=%22Trojan+Horse+Of+Viruses+Revealed%22&btnG=Google+Search

That's an excellent title for an article about the paper.


Also, another layman's article summarizing the paper has spread, here is a link googling: "Dirty Rotten Poxviruses"
http://www.google.com/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&q=%22Dirty+Rotten+Poxviruses%22&btnG=Google+Search


In "Dirty Rotten Poxviruses" the author writes,
"poxviruses have engineered a way to sneak into cells through the garbage chute."
and - "the virus disguises itself as junk"

Again, great writing!
It can't be said much more simply than that.

She also writes,
"the team wondered if the virus was playing dead. They found that the virus's surface was studded with phosphatidylserine, a lipid that also flags dead cells as garbage. Removing lipids from the virus's surface stopped infection, and recoating the virus with phosphatidylserine restarted it. The results suggest that the virus is "more clever than originally thought" because it exploits a garbage-collection process found in almost all cells, says Mercer.


"phosphatidylserine, a lipid that also flags dead cells as garbage."

perfect!




------------------------------------




The next month, the journal Nature picked up the new insights into PS facilitated viral infection and immune shut-off.



NATURE REVIEWS: Molecular Cell Biology, June 2008



Virus plays dead



http://www.nature.com/nrm/journal/v9/n6/full/nrm2420.html



Research Highlight

Nature Reviews Molecular Cell Biology 9, 422 (June 2008) | doi:10.1038/nrm2420

Cellular microbiology: Virus plays dead

Arianne Heinrichs



Vaccinia virus is a large, complex, enveloped DNA virus that belongs to the Poxviridae family of viruses, which includes variola, the causative agent of smallpox. The infectious mature virus (MV) form of vaccinia has been shown to bind to actin-containing finger-like protrusions (filopodia) of the host cell and enter the cell in a pH-dependent manner. In a new study published in Science, Jason Mercer and Ari Helenius report that the MV form of vaccinia virus enters host cells using macropinocytosisand apoptotic mimicry.

The authors prepared fluorescent MV particles and used live imaging to follow the entry of individual particles into host cells that expressed fluorescent actin. Virus particles that bound to filopodia moved towards the cell body in an actin-dependent manner. Once they reached the cell body, membrane blebs formed at the site of contact with virus, followed by the formation of further blebs along the entire cell body. The blebs eventually retracted, which coincided with virus entry. Inhibiting membrane blebbing caused a large reduction in infection, which suggests that blebbing is required for infection.

The Ser/Thr kinase p21-activated kinase-1 (PAK1) is essential for MV infection; indeed, knockdown of PAK1 reduced infection significantly. MV infection is accompanied by phosphorylation of residue Thr423 of PAK1, which is known to be essential for macropinocytosis. PAK1 knockdown studies also showed that PAK1 is required for events that occur prior to viral fusion, including blebbing. Perturbance of several other factors, including the PAK1 activator GTPase Rac1 and Na+/H+ exchangers, inhibited both blebbing and infection. This further confirmed that these processes are linked. Sensitivity to Na+/H+ exchangers is also characteristic of macropinocytosis. Indeed, MVs co-internalized with fluid-phase cargo, but not clathrin-dependent cargo, in a macropinocytosis-type endocytic process.

Apoptotic bodies are macropinocytosed by phagocytes and other cell types, and uptake of apoptotic debris is triggered by the presence of exposed phosphatidylserine (PS) on the plasma membrane. The MV membrane is known to be enriched in PS, which is required for infection. The authors showed that PS is exposed on the MV surface and that virus particles extracted with a detergent that removes all lipids fail to induce blebbing and infection. Reconstitution of the extracted virus particles with PS restored infection. Because MVs are comparable in size to apoptotic bodies and the uptake mechanisms are the same, Mercer and Helenius concluded that viral PS might be analogous to cellular PS and triggers the uptake of virus particles by mimicking apoptotic bodies. Consistent with this, late-stage vaccinia-infected cells were shown to undergo apoptosis.

The clever use of apoptotic mimicry and subsequent entry by macropinocytosis allows large particles such as vaccinia virus to infect many different potential host cells. And by posing as apoptotic bodies, MVs may also avoid immune detection.


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IT'S HAPPENING! :)


j