4 - Host Response to Virus/How Viruses Escape

Question 1

What are the host defenses against a virus infection?

Answer 1

Natural barriers: skin, mucus, ciliated epithelia, bile, secreted IgA, Type 1 IFN response: innate

Question 2

What are the three responses our bodies can have to a virus?

Answer 2

Innate: cytokine response, NK response, complement

Adaptive immune response: cytokines, T cells, B cells (antibodies)

Apoptotic resposne

Question 3

Describe the early anti-viral host defense that occurs?

Answer 3

Innate response: production of IFN-a, IFN-B, and IL-12. NK cell killing of infected cells.

This occurs from days 1-5 of the viral infection.

Question 4

What can different interferons be used to treat? Why aren’t they routinely used to treat viral infections since they drive a Th1 immune response?

Answer 4

a: Hep C, melanoma, and some leukemias.

B: MS

Y: limited usefulness.

IFNs cause flu-like symptoms following each injection and can cause problems with thinking and concentrating. Can also reduce blood counts.

Question 5

What is a type I interferon response that occurs in in a virus infection? Where are type I interferons found? Where are type II interferons founds?

Answer 5

Release of IFN-a and IFN-B that results from pattern recognition receptors binding PAMPs on a virus.

Type 1 interferons are found in all cells. Type 2 interferons are immune interferons found in T and NK cells.

Question 6

What are the steps in a type 1 interferon response?

Answer 6

1. Viral products sensed by PRRs such as TLRs.
2. Cascade of signaling through kinases
3. Activation of TFs
4. Synthesis and secretion of IFNa/B (induction of the antiviral state).

Question 7

What do type 1 interferons activate?

Answer 7

Protein kinase R (PKR), which binds dsRNA and is autophosphorylated (its a PRR!)

Then it phosphorylates eIF-2a which delivers MET tRNA to the 40S ribosome to initiate polypep synthesis.

When eIF-2a is phosphorylated, translation is inhibited and protein synthesis is shut down.

Question 8

Other than PKR, what else is activated by type I interferons?

Answer 8

Oligoadentylate synthase (OAS): binds dsRNA and catalyzes synthesis of oligoadenylate from ATP.

Oligo AAAA activate RNAse L via dimeration and RNAse L degrades mRNA.

Question 9

What is increased during the anti-viral state? What is decreased?

Answer 9

Increased: MHC class 1 expression and surface class 1 MHC, PKR, 2’-5’ synthase expression, 2’-5’ oligo A(A-A), viral mRNA degradation, and increased NK cells.

Decreased: viral protein synthesis

Question 10

What cytokines are involved in the innate immune response?

Answer 10

TNFa, IL-1B, and IL-6

IL-12 promotes NK production of IFNY

IL-2 promotes NK prolif

Question 11

What is the function of TNFa? What produces it?

Answer 11

Pyrogen - induces fever

Produced by activated mø, CD4 T cells, and NK cells.

Major pro-inflammatory cytokine.

Question 12

What is the function of IL-1B and? What produces it?

Answer 12

Pyrogen - induces fever

Produced by secreted activated mø.

Major pro-inflammatory cytokine.

Question 13

What is the function of NK cells in the innate response to a virus?

Answer 13

They balance excitatory and inhibitory signals.: inhibitory from class 1 molecules, activating signals from NK activating ligands (which are up-regulated in response to a virus infection).

Question 14

What is the function of the adaptive immune response to a virus infection? When does this occur?

Answer 14

Eradication of the virus.

This occurs later in the virus infections (around day 4)

Question 15

Infected cells are often induced to undergo apoptosis, what induces them to do this?

Answer 15

From within: protective, “selfless”, infected cell reponse.

From without: TNF-a, cytotoxic T cells, NK cells.

Question 16

What is the function of Bcl-2? What protein does the opposite?

Answer 16

It’s an IAP - an inhibitory of apoptosis protein

p53 when up-regulated causes growth arrest and apoptosis.

Question 17

What is the function of Interleukin-converting enzyme (ICE)?

Answer 17

It’s a caspase (caspase-1) that cleaves pro-IL-1B to activate IL-1B, which causes inflammation that has disastrous consequences

Question 18

How do viruses handle interferons?

Answer 18

They encode proteins that prevent IFN binding.

Question 19

List five examples of viral inhibitors of interferon-induced antiviral response done by adenovirus, poxvirus, and herpesviruses?

Answer 19

1. Proteins direct phosphoatases to dephos. eIF-2a (herpes)
2. “decoy” structured RNA binds to PKR and prevents activation by viral dsRNA (adeno)
3. dsRNA bps sequester dsRNA and prevent PKR activation (pox)
4. eIF-2a decoys bind activated PKR to prevent it from acting on eIF-2a (pox)
5. Decoy receptors bind IFN and sequester it (pox)

Question 20

How do viruses respond to pro-inflammatory cytokines?

Answer 20

They encode IL-1B bps that soak up IL-1B.

They also encode soluble TNF receptors.

Question 21

How do viruses effect complement?

Answer 21

Can encode homologs of complement control proteins that prevent the assembly of MAC complex.

Can encapsidate viral or host complement control proteins in membraned to evade complement-mediated lysis.

Question 22

What are some viral means of affecting the surface expression of class I MHC molecules?

Answer 22

1. Degrade TAP transporter
2. Block peptide transport into ER by blocking TAP transporter
3. Degrade class I MHC
4. Retain class I MHC in ER/golgi
5. Divert class I MHC to lysosomes (HIV)
6. Downregulate transciprtion of components of the MHC molecules (adenovirus)

Question 23

What can HIV vdo to evade NK cell killing?

Answer 23

Modulate removal of MHC-1 from surface of infected cells, remove some HLA-A and -B but leave HLA-C on the surface of infected cells.

Question 24

What other ways can viruses evade NK cell killing?

Answer 24

Encode decoy MHC-I-like molecules that interact with inhibitory NK receptors.

Prevent activating NK cell receptor ligands from arriving at cell surface but retaining them in the ER or sending them to the lysosome.

Question 25

Viruses induce the down-regulation of other molecules in the immunological synapse, what are these molecules?

Answer 25

Adhesion molecules and co-stimulatory molecules.

Question 26

How do viruses deal with infected cells potentially undergoing apoptosis?

Answer 26

Viruses encode many inhibitors of apoptosis (IAPs).

Question 27

What are the mechanisms by which viruses avoid cellular apoptosis?

Answer 27

1. Virus-encoded soluble TNF receptors
2. Caspase inhibitors that block proteolytic steps of caspase activation and target protein cleavage
3. Homologs of anti-apoptotic proteins such as Bcl-2
4. Inhibitors of p53, a major inducer of apoptosis from within

Question 28

Why don’t viruses want their host cell to die?

Answer 28

Because they need to propagate within the host cell and if the host cell commits suicide, the virus can’t achieve its goal.

Question 29

What are some characteristics that make viruses stealthy?

Answer 29

Latency, epitope miutation, infection of privileged sites, intracellular sequestration, infection via immune receptors.

Question 30

How does the set-point of the immune/inflammatory response determine health or disease for virus infection?

Answer 30

Too little host defense and the virus takes over.

Too much inflammatory response causes severe disease.