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123 Cards in this Set
- Front
- Back
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What are the 2 strategies a virus may use to infect a host?
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Hit and run
Hit and stay |
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What is the hit and run strategy?
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Cytolytic infection
Highly infective virus propagates before being eliminated by CMI |
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What are some examples of viruses that use the hit and run strategy?
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Influenza
Rhinovirus Measles |
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What is the hit and stay strategy?
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Long term residence in the host
Latency, inapparent infection of host immune control achieves a tolerable disease state Frequent/infrequent transmission: infection is more frequent when the virus is not latent |
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What are some examples of viruses that use the hit and stay strategy?
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HepB
HSV HHV-8 |
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What are passive evasion strategies?
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General aspects of viral replication in the host that contribute to viral evasion
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What are examples of viral passive evasion strategies?
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Envelope
Non-cytopathic infection (no death) Cell-to-cell viral spread Growth in priviliged tissues (tropism) Latent infection |
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What kind of tropism does CMV cause?
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Infection in salivary glands
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What kind of tropism does HPV cause?
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Infection of the outer skin layer (causes warts)
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Where does Rubella cause a tropism?
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In the developing fetus
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What strategy do most herpesviruses employ?
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Latent infection
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What are the active immunoevasive mechanism of viruses?
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-Change in the antigenic repertoire
-Active manipulation of host cells and immune fct |
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How can the virus change the antigenic repertoire?
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-Antigenic Drift
-Antigenic Shift |
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Which viruses use Antigenic drift?
What happens in this strategy? |
RNA viruses with low fidelity RNA pol (Pol that has no proofreading activity .: eventually some virus can come out that the IS won't recognize)
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What happens during antigenic shift?
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Exchange of a whole RNA segment of the genome --> new viral strain
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What is more virulent: Ag drift or Ag shift?
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Ag shift
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How can a virus actively manipulate the host cell and immune fct?
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Interference with cytokine signalling
Impairement of recognition by IR (impairement of MHC I & II Ag presentation) |
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What are some Orthomyxoviruses?
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Influenza
Thogoto Isavirus |
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What kind of viruses are orthomyxoviruses?
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Negative strand RNA
Segmented |
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How many types of Influenza viruses are there?
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3: A, B, C
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What ptn do all influenza viruses encode?
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NS1
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What segment encodes NS1?
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Segment 8 (the smallest segment)
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What is NS1 important for?
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One of the main determinants of viral evasion
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What host cell receptor recognizes infection by Influenza?
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RIG-1
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What happens once RIG-I rec'z the virus?
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Induction of a strong IFN response
--> Can clear the virus |
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Why can influenza be so pathogenic, if the body can respond to it?
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NS1 inhibits the immune response
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What happens if you put silencing RNA next to RIG-I?
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Everything changes
There is no more IFN-response genes No TNF-a (.: NF-kB signalling is also impaired) |
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What does NS1 specifically inhibit?
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IFN response
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EXP'T
What happens if heat-inactivated virus is injected into WT mice? |
Get type-1 IFN induction
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EXP'T
What happens when live WT virus is injected into WT mice? |
No IFN induction .: death
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What happens if NS1 deleted virus is injected into WT mice?
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Get IFN induction
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What happens if deleted NS1 virus is injected into STAT-1 KO mice?
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Get death of mice
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Which stage of IFN induction does NS1 inhibit?
How do we know? |
Early steps
-->If WT virus injected into WT mice: get poor IFN production, poor NF-kB, IRF3 and AP-1 activation -->If delNS1 virus is injected into WT mice: get high IFN production, High NF-kB, IRF-3 and AP-1 activation |
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Does NS1 only inhibit IFN production?
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No, it works at multiple levels
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What are the multiple levels that NS1 acts at?
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Inhibits early IFN production
Inhibits mRNA processing Inhibits PKR |
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How does NS1 inhibit mRNA processing?
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C-terminal inhibits polyadenylation
N-terminal interacts with snRNPs, inhibiting splicing Inhibition of mRNA transport |
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How does NS1 inhibit PKR?
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Inhibits transcriptional induction
Sequesters dsRNA =>This keeps cells in active Translation and ends up only Tl viral RNA |
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What does NS1 interact with and with what part of its structure?
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RIG-1: through its RNA-binding domain
dsRNA: through its RNA binding domain PKR: through its effector domain |
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How does NS1 inhibit the activation of RIG-1?
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Binds RIG-1 and inhibits P of IRF3 and all other paths downstream
This is probably RNA dependent |
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What happens when NS1 binds PKR?
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Blocks P of eIF2A .: don't get Tl of host ptns
Everything that will be Tl is viral ptns This is RNA independent |
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What happens when NS1 binds dsRNA?
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Inhibits OAS activation
--> makes dsRNA become invisible .: OAS has nothing to bind to .: can't cause its polyA and RNAse L remains inactive RNA dependent mechanism |
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Which region mediates the direct interaction between NS1 and RIG-1?
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Same region in NS1 that binds dsRNA
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What happens to host cytokines and IR if NS1 is deleted from influenza?
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Get increase in both IFN-B and TNF-a
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What does NS1 block in the host IR?
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IFN-B
TNF-a NF-kB activation in infected cells |
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Describe the Hepatitis C virus
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Positive, ssRNA
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What kind of pathology does Hep C cause?
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Liver disease
Liver cancer |
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What is the current therapy for hep C infection?
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IFN + Ribavirin
=>Not very successful, only 15-20% erradication The rest of the ppl develop chronic infection Hep C mutates very quickly and develops rapid resistance |
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Which receptors on the host recognize HCV RNA?
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RIG-I
TLR3 PKR (also TLR7) |
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Which ptns in HCV block RIG-I and TLR3? (.: don't get type-1 IFN production)
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NS3/4A
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Which ptns in HCV block PKR signalling?
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E2
NS5A |
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What is the result of E2 and NS5A blocking IFN PKR singalling?
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Don't get a block in viral ptn synthesis
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Which ptns in HCV inhibit IFN signalling?
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NS5A
Core ptn |
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How do NS5A and the core ptn interfere with IFN signalling?
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Inteferes with the JAK-STAT path
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What kind of a ptn is NS3/4A of HCV?
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Protease
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What does NS3/4A do?
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Cleaves MAVS (at cystein 508, at hte C-terminal)
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What happens when MAVS is cleaved?
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Cannot be localized to the mitochondria
.: IFN signalling is blocked MAVS localized instead to the cytoplasm |
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What is the result of MAVS being relocalized to the cytoplasm, instead of the mitochondria?
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Prevent activation of RIG-I and .: prevents downstream signalling
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What happens if you have an NS3/4A that is mutated so it no longer has a protease activity?
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Nothing happens to MAVS when this NS3/4A is cotransfected (.: we know that it is NS3/4A that is responsible for MAVS cleavage)
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What happens if the cystein 508 (right before that transmb domain) in MAVS is changed to an arginine?
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No longer get cleavage by NS3/4A
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What family does the hantavirus belong to?
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Bunyaviridae
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What kind of virus is the Hantavirus?
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Negative stranded RNA virus
Segmented |
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How does the Hantavirus evade the IS?
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Replicated within vascular endothelial cells
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What kind of pathology does the Hantavirus cause?
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Hemorrhagic fever
Pulmonary disease |
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What do the pathogenic strains of hantaviruses (NY-1V) do?
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Inhibit IFN
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Do non-pathogenic strain (PHV) inhibit IFN?
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No
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What does the Hantavirus induce production of?
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MxA
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What's the difference between the non-pathogenic strain and the pathogenic strain of Hantavirus when it comes to MxA production?
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Non-pathogenic strain: get MxA production really early on
Pathogenic strain: MxA production is delayed |
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What does MxA do?
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Interacts with N ptn and sequesters it so new particles can't be formed (same mechanism of Crimean congo virus)
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What hantavirus ptn interacts with TRAF3?
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GN ptn
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What happens when the GN ptn interacts with TRAF3?
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Inhibits TBK-1 activation
.: no ISRE activation .: no IRF3 ==>Get very early block of the IFN system |
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What is TRAF3 for?
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Central mediator of activation of IKKe and TBK-1
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What happens without TRAF3?
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No downstream signallling
-->Never even make MxA |
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What happens in MHC presentation during normal viral infection?
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Virus comes in, makes its viral ptns
These ptns get chopped up by the proteasome Get little peptides that are imported to the ER lumen by TAP system MHC I molec that are the loading site of MHC are facing the lumen Peptides get loaded onto MHC-I, makes it to the cell surface ->Signal adaptive immunity |
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How does HHV7 prevent MHC I AG presentation?
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Takes MHC-I out of the golgi and sends it to the lysosome for degradation
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How do HHV8 and HIV prevent MHC I Ag presentation?
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Take MHC-I off the surface and lead it to internalization through the lysosome
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How does EBV prevent MHC I Ag presentation?
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Uses its ptn EBNA-1 to block degradation by the proteasome
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How does HCMV prevent MHC I Ag presentation?
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Encodes ptns (US2, US11) that send MHC out of the ER and into the cytoplasm
There, it is recognized as mislocated and .: degraded |
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How do the Adenovirus and HSV prevent MHC-I Ag presentation?
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Block the translocation of the little peptides into the lumen by blocking TAP
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What are the mechanisms of inhibition of MHC I?
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Target MHC-I surface molec for degradation via ubiquitin ligase activity
Inhibition of peptide loading by inhibiting Tap or Tapsin Retention of MHC I in the ER Ejection of MHC-I ptns from the ER to cytoplasm |
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What 4 ptns does HCMV produce to interfere with MHC I?
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US6
US3 US2 US11 |
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Which HCMV ptns block the import of Ag peptides?
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US6
US3 |
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How does US6 work?
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Binds TAP system
Prevents loading of ATP .: stalls peptide translocation to ER |
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How does US3 work?
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Binds tapsin .: molecules that get loaded onto tapasin can't bind to MHC
Binds transmb domain of MHC I molec and prevents translocation to golgi and blocks its export to the plasma mb |
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What does US2 of HCMV do?
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Binds to the B2m and translocates molec from the ER --> cytoplasm
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What does US11 do?
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Transports MHC out of ER into the cytoplasm
->Once MHC is in the cytoplasm, it gets sent to the proteasome because its not supposed to be in there |
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Why is it important that viruses inhibit MHC I?
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MHC I important to signal that something is wrong in the cell
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HIV and MHC I
What does the HIV ptn Nef do? |
Causes endocytosis of MHC I --> Goes to endosome
Inhibits transport of MHC I to cell surface (in T cells) |
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HIV and MHC I
What does the HIV ptn Tat do? |
Works at promoter level, inhibits MHC-1/B2m
--> .: decreases availability of MHC-1 molecule Inhibits proteasome .: can't makes little viral peptides -Inhibits MHC II by sequestering CIITA |
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Which HLA's does HIV work on?
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Only HLA-A/B
(not HLA-E/C) |
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Why doesn't HIV downregulate the HLA E/C?
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Because then NK cells would recognize that there was a problem with the cell
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How can viruses inhibit cytokine signalling?
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Use viral ptns that mimic host ptns
--> Only large viruses can do this |
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What type of viruses encode ptns that mimic ligands and receptor of cytokine signalling?
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Poxviruses
Herpesvirus (Large DNA viruses) |
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Why can large DNA viruses only have these mimicry ptns?
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They are large enough to encode a lot of non-structural ptns
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What do herpesviruses have?
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Viral homologues
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What do poxviruses have?
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Secreted ptns that bind cytokines or chemokines
(ex: HIV Tat, RSV G-ptn) |
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What do virokines and viroreceptors do?
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Modulate cytokine activity during infection
(Encoded by pox& herpesviruses) |
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What do virokines and viroreceptors act as?
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Immune evasion: inactivate inflam cytokines or redirect IR
Induction of cell proliferation Induction of cell migration after infection Enhancement of viral replication |
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How are virokines and viroreceptors acquired?
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1-Viral piracy (incorporated genes from host, herpesvirus)
2-Evolved separately (poxvirus) |
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Where is vIL-10 found?
What does it do? |
EBV, HCMV
-Anti-inflam -Suppression of macs -APC activity |
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Where is vIL-6 found?
What does it do? |
HHV-8
Acts as a growth factor for infected B cells and contributes to lymphocyte dev'p Pro-inflam |
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Why would HHV8 want to stimulate infected B cell development?
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Activate B cell to undergo replication so all the Tl machinery can be used
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Where is VGF found?
What does it do? |
Vaccinia
-Homologue to cellular EGF -No immune modulation activity Increases cellular replication and activates Ras because actively dividing cell needs a high nucleotide pool, which is also what Vaccinia needs |
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What kind of virokines/viroreceptors does the Poxvirus encode?
What does this result in? |
Homologue of soluble receptors of transmb domains
No signalling activity of viral receptors, just suck up all the chemokines ==> Shut down host cytokine signalling |
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What are the viral soluble cytokine receptors of Poxviruses?
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vTNF-R
vIL1B-R vIFN-yR |
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What do these soluble cytokine receptors look like?
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Have a sequences similarity to the extracellular domain, but no transmb and signalling domain
.: Have no real homology to cellular ptn, but are characteristic of pox virus |
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What do these soluble cytokine receptors do?
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Bind cytokines with great affinity and neutralize their activity
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What does vCSF1-BP of EBV modulate?
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Macrophage response
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How does the vaccinia virus (part of the pox family) use a viral soluble cytokine receptor to inhibit IFN?
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Cell is infected with Vaccinia
Vaccinia produces and IFNa/B binding ptn This ptn binds the mbs of neighboring cells .: when infected cell makes low level of IFNa/B that goes around to activate JAK-STAT, it will be taken up by the soluble BP and uninfected cells will not realize that infection has occured -->Thse cells won't be able to cause an antiviral state |
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Do viral chemokine homologues fct as agonists or antagonists?
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Depends on what virus wants to do
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What kind of viral chemokine homologue is vMIP-2 (HHV8)?
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Broad spectrum chemokine antagonist
-->Immune evasion |
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What kind of viral chemokine homologue is U83 (HHV6) and Tat (HIV)?
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Induce monoycte migration
-> Establishment of latency (HHV6) -->Cause viral replication (HIV) |
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What kind of viral chemokine homologue is vMIP1 and 2 (HHV8)?
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Chemoattractants for Th2 cellls
-->Influence the type of response to viral infection (Th2 response this virus does nothing and prevents a Th1 response, which is what is needed to get rid of this virus) |
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Where are the viral chemokine receptors of the herpesvirus expressed?
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Only on infected cells
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What do the viral chemokine receptors ORF7 and vGCPR (of HHV8) do?
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Constitutively active
Induce cell prolif and NF-kB activation --> Pro-inflammatory and pro-angiogenic |
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What does the viral chemokine receptor U51 (of HHV6) do?
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Reduces extracellular accumulation of RANTES by sequestering it and downregulating transcription
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What kind of activity do agonists have?
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Positive activity
Cause target cells to migrate |
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What kind of activity do antagonist have?
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Negative
Don't attract lymphocytes to site of infection |
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How can a virus inhibit apoptosis?
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Inhibit specific steps in the capase or mitochondrial path
Inhibit p53 Activate pro-survival paths such as NF-kB |
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How does HHV-8 inhibit apoptosis?
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Inhibits Caspase 8 activation
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How does EBV inhibit apoptosis?
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Inhibits it at the mitochondrial level (uses BALF and BHRF1 to work on Bcl2 and BCLXL)
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How does HPV inhibit apoptosis?
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Inhibits p53 and Rb(retinoblastoma)
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What is the point of apoptosis of infected cells?
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Limit viral replication if everything else fails
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Read paper referenced on the last slide
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Read paper referenced on the last slide
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