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76 Cards in this Set

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Describe the basics of retroviral replication (ex: HIV)
Entry through specific recognition
-Requires receptor-ligand interaction
Get several virus-host interactions
There is a nucleus intermediate for retroviruses viruses that have to be converted into DNA
Then the viral DNA gets converted into the host DNA
Needs many ptns to get viral escape
Then get budding and viral maturation
What type of host factors are co-opted by HIV-1?
Many that are involved in viral assembly etc
What are HMGA and LEDGF/p75 used for?
Nuclear entry/import
What do the ESCRT ptns do
Cause invagination
Important for multiple body formation
Why does the virus co-opt ESCRT ptns?
Allow viral budding from host cell surface
What are siRNA screens?
Knock down each gene in the host cell and see if it plays a role in HIV replication
What was found when they did a genome-wide siRNA screen to test for HIV co-opting?
Found that over 200 host genes take part in generating viral particles
What is the receptor of HIV?
CD4
What is one of the coreceptors for HIV?
CCR4
What is one way of targeting the host cell fct to inhibit HIV RNA export?
Block Rev-mediated RNA export by blocking the modification of spermidine
-Inhibit hypersination of eIF5A
What does eIF5A do?
Involved in export of viral RNA
Block this molec, can block viral replication
What drug is used to exert this fct?
Semapimod
What drug can target a host cell fct to inhibit HIV-1 DNA integration?
KU-8593 cmpd
What does this drug do?
Targets the step right after integration
Virus takes advantage of the DNA repair mechanism to insert itself into the host genome
The KU-cmpd blocks this repair mechanism
==> Stop the virus, but also kill the host cell (ass't with toxicity)
What is the fct of the cytoskeleton network?
Maintain cell morphology: structural elements in cellular organelles
Transport of cellular macromolec, vesicles
Exocytosis; synaptic transmission
Maintain cellular ptn and RNA interactions (ex: RNPs)
Regulation of gene expression (translation), nuclear export of RNAs, post transcriptional and post-translational modifications
What does actin polymerization lead to the formation of?
Intermediate and micro-filaments
ex: HIV-1, retroviruses, vaccinia virus, HTLV-1
What does tubulin polymerization lead to the formation of?
Microtubules
ex: vaccinia virrus, HIV-1, HTLV-1
What is the difference between actin and microtubules?
Actin has a dense cortical network
Mts have polarity and work in cell division
What do Mt serve for?
Highway from nucleus to plasma mb
-->but first have to penetrate through/around actin to get onto the mt to get to the nucleus
What is actin important for?
Viral assembly:
-network to facilitate viral assembly at the appropriate sites
-maintenace of virus integrity and structure
-enhance possibility of molecular interactions (assembly)
Macromolecule and vesicle transport: roles in directing traffic of intracellular organelles, vesicles, structures, RNPs
Trafficking viral components (RNA, ptn) to assembly sites (viral ribonucleoptn (RNP) complexes)
.: Actin important for virus assembly, transmission and dissemination
How does Ravovirus use actin to its adv?
Uses it for viral dissemination
How does paramyxovirus use actin?
Transport nucleocapsids to the cell surface and get their budding
Movement of enveloppe ptns to plasma mb
Actin binds RNP complex and induces conformational changes that are required for transcription
Cytochalasin B completely inhibits viral particle release
How does the poxvirus (vaccinia) use actin?
Induces polymerization of actin into a tail structure directly behind the virions
Propels virions forward
Use this to propel virus outwards upon cell contact and infect neighboring cells
How does the retroviridae use actin?
Virus particles are present at the tips of actin containing projections
How do mammalian containing retroviruses use actin?
Induce actin projections which contact the virions
Use actin and myosin for last stages of viral release
How pertinent is cytoskeleton interactions in vaccinia virus replication?
1) Need it for intracellular assembly and viral movement by mediating actin polymerization behind viral capsid
VV mimics signalling and P event to promote actin polymerization
2) This promotes viral budding from actin-rich microvilli
-->Propels virus capsid to outside thereby getting large profuction and dissemination of the virions
What does actin as't with in HIV?
Ass'ts with viral structural ptns
Colocalizes with actin microfilaments in cells and with inner core in retroviruses
What are some host ptns that can be found in HIV after infection?
G1PDH
Actin
Cofilin
Epin/Moesin
What are some useful drugs used in experiments to disrupt actin?
Wortmannin
Cytochalasin D
Latruculin B
Swinholide A
Taxol
Nocodazole
Colcemid
Jasplakinolid
What does wortmannin do?
Disruption of myosin-actin based motility by inhibiting myosin kinase activity
What does cytochalasin D do?
Disruption of actin-based cytoskeleton
Depolymerizes actin (intermediate filaments, microfilaments are polymers of actin)
->Blocks viral exit
What do Latruculin B and Swinholife A do?
Depolymerizes actin
Disruption of actin-based cytoskeleton
What do Taxol and Nocodazole do?
Disassembles the tubulin based cytoskeleton (MT)
What does Colcemid do?
Depolarizes Mt
Blocks transport on Mt
What does Jasplakinolide do?
Polymerizes and stabilizes actin-based cytoskeleton
"Freezes" it
Can any of these drugs be used clinically?
No because they are too toxic
would also target host
What steps of viral replication are influenced by the actin cytoskeleton?
Transcription
Viral infectivity
Transport
Assembly
Viral release
Virus budding
Structural role
-->Also later involved in viral transmission and receptor recruitment
What are the 3 mechanisms of HIV-1 transmission?
1) Free virus receptor mediated entry
2) Entrapped cell-cell
3) Veritable cell-cell
Describe the free virus receptor-mediated entry mechanism
Free virions attach to the cell surface receptor (Envelope attached to the CD4 receptor)
Uncoating and entry
Describe the entrapped cell-cell mechanism
Virus is trapped and engulfed by macs and DCs
Can live in large compartment of the cell
The immune cell travels to LN or other immmunoprivileged areas of the body and can transfer the virus from the phagocyte to other cells
Describe the veritable cell-cell mechanism of transmission
Infected T cell can sample uninfected cells
Creates a bridge and mediates transmission through a synapse
What happens in cell-cell transmission?
Get recruitment of receptor and ligand
Ligand-receptor pair recruited to the area btw uninfected and infected cells
Coreceptor CXCR4 is also capped at this site during the cell-cell contact
Get recruitment of receptors specific to cells infected with HIV
What is the actin receptor?
Talin (actin anchor ptn)
-->Co-capped in viral envelope
What adhesion molecule is involved in cocapping?
What does it do?
LFA-1: receptor for adhesion molec (ICAM)
What happens to these receptors during cell-cell transmission?
Active recruitment of ligand-receptor complx
Also get structural component between ICAM and LFA-1
What does cytochalasin D do?
Actin polymerization inhibitor
What did addition of Jasplakinolide do to HIV?
Polymerizes and stabilizes actin (freezes actin where it is)
No longer get capping of env-CD4 pair
What about actin is important to HIV?
Actin-cytoskeleton integrity
Receptors need to be actively trafficked to the area
Why does HIV use immune sampling? (uses host immune cells to sample the env't)
-Promote transmission of virus from infected cells to non-infecte cells
-Might be in an immunoprivileged site (might be able to the evade immune surveillance)
What is the method of transmittance of HTLV?
Only cell-to-cell
How is HTLV transmitted from cell-cell?
Uses a virological synapse
What contributions does actin make to HTLV pathogenesis?
Cytoskeletal rearrangement and recruitment to cell-cell jcts
Involvement of mt (use of nocadazole)
Virus particles or Gag/RNA in virological synapse
What is suggested since since the talin actin receptor is used in co-capping at the site of inflammation?
Active recruitment of receptors is actin dependent to promote viral dissemination
What happens to the major structural ptn of HTLV?
It is capped
--Transfer due to the rearrangement of mt due to cell-cell contact
Describe cell-cell transmission in HTLV
Infected cell meets uninfected cell
Recruitment of mb receptors
Reorganization of cytoskeleton
Recruitment of MTOC (and other things like adhesion molec) to site of cell-cell contact
Viral ptn and genome trafficking
Recruitment of mb receptors
Formation of virological synapse
Virus transmission (ex: HIV, HTLV, possibly SARS and HSV too)
--Need means to evade the host immune response and enhance viral propagation
-Enhance rate of infection
What does virus cell surfing of MLV, HIV and ALV do?
Allows virus to traffic to actin poor (and remodelling) regions to facillitate entry via myosin II-actin dependent mechanisms
What are cell filopodia used for?
They are cellular extensions
Another way to cause viral dissemination
Where do the filopodia form?
What do they do?
Extend from the UNINFECTED cells, reach over and capture virus particles that are being produced by the infected cells
What are the advantages of using this system?
Avoid actin-rich filopodia that could prevent infection
Traffic to areas where endocytosis occurs and/or to areas of the cell (i.e. the cell body) where actin is constantly being remodelled
Enhance infection efficiency: highway to the cell
Myosin motor and actin-dependent mechanism
What is necessary for virus surfing on filopodia?
Receptor ligand/Envelop anchoring is necessary
What are the ligands and receptors for this surfing?
mCAT is the receptor for the MLV envelope
What happens if anti-env Ab were added to the mix?
Neutralization
-->Disrupt formation of filopodia bridges btw uninfected and infected cells
What is the point of virus surfing on filopodia?
Facilitate viral entry
Where is the virus located when it surfs on filopodia?
Virus is on the outside surface and is exposed to the outer milieu
What are nanotubes?
Used in T cells
Extension between BOTH the cells (protrude from the uninfected AND infected cells)
Don't form a continuous channel, but actually 2 separate ones
Virus travels along the surface of these and infects the uninfected cell
How are filopodia/cytonemes formed?
Not formed when the 2 cells collide
Stabilized by ligand-receptor interaction
Coated Pit tether, but not critical
How are nanotubes formed?
Formed when cells collide
Not stabilized by ligand-receptor interaction
Coated pit tether
What is the speed at which filopodia extend?
0.03um/sec
What is the speed at which nanotubes extend?
0.08 um/sec
Are filopodia and nanotubes pliable over long distances?
Yes
How is the virus transmitted along filopodia?
Depends on CD4/Env
Receptor-dependent
Virus on outer surfac of extension
Not a continous tunnel
Depends on actin-myosin II
Extends ONLY from uninfected cells
Cells don't need to touch to form filopodia
How is the virus transmitted along nanotubes?
Depends on CD4/Env
Receptor dependent
Don't really know where virus is, but probably on the outside
Not a continuous tunnel
Depends on actin
How are Prions transmitted?
Via nanotubes
Mechanism may involve direct tunnelling between cells (continuous)
What happens to actin in a vaccinia virus?
Get an Actin comet
-->Comet propels virus towards uninfected cells
What happens to actin in African swine fever virus?
Propulsive filopodia/mbs
What are some advantages to the virus dissemination strategies as cell-to-cell transmission via the virological synapse?
Enhance efficiency and rate of transmission
Immunological escape mechanism