Viruses and the immune system Flashcards
1
Q
What is the purpose of the innate immune system?
A
Clear infections if there is a low dose challenge
Slow infections until the adaptive immune response ins activated
2
Q
How does complement defend against viruses?
A
Not that important in a primary infection, though is useful in secondary infection along with antibody complexes
Opsonise particles: promote phagocytosis of infected cells or virus by cells with complement receptors
3
Q
How do viruses use/evade complement?
A
Retroviruses activate it directly - thought increase cell tropism range
Use complement proteins as receptors
Evade complement e.g. VACV complement control protein
4
Q
How do natural killer cells defend against viruses?
A
Have an Fc receptor
Kill cells if there is decreased MHC-I expression (some viruses down regulate)
Receptors that recognise stress proteins (including influenza HA and NA) and kill cells
5
Q
How do NK cells kill?
A
Activated by IFNalpha/beta. Release cytocidal proteins in lytic granules e.g. perforin and granzymes
Upregulate Fas L and TRAIL
Accumulate by chemoattraction and proliferation
6
Q
What cytokines/chemokines do NK cells produce?
A
Activated by IL-12
Early producer of IFNgamma (skews towards Th1)
Also makes TNFalpha and cytokines for immune cell survival
7
Q
How do NK cells interact with dendritic cells?
A
DC production of IL-12 and IFNalpha/beta activates NK cells
NK cell production of TNFalpha triggers DC activation
8
Q
What is the importance of NK cells in the defence from viruses?
A
Lack of NK cells results in potentially lethal infections of VZV and HCMV in humans and mice (MCMV).
9
Q
How do macrophages defend against viruses?
A
M1 macrophages are useful - stimulated by inflammatory signals
Phagocytose opsonised infected cells and virions; up regulate IL-12; phagocytosis of infected cells limits inflammation (no killed cell contents released)
Antigen presenting cell for adaptive immune response
10
Q
What do type 1 interferons do?
A
Includes IFN alpha and beta. Are induced (through PRRs, TLRs and IRF3/NFkB) secreted from virus infected cells and induce an antiviral state in neighbouring cells through the JAK/STAT signalling pathway (inducing ISGF-3 entering the nucleus as a dimer and binding ISRE at gene promoters), triggering the production of interferon stimulated genes
11
Q
What does OAS do?
A
Oligoadenylate synthesise - an interferon stimulated gene. Activated by dsRNA. Makes oligoadenylate oligomers which activate RNAse L
12
Q
What does RNAse L do?
A
Activated by OAS. Cleaves ssRNA. OAS remains located near dsRNA, so RNAse L cleaves ssRNAs near the dsRNA.
13
Q
What does PKR do?
A
Activated by dsRNA. Phosphorylates itself to active, phosphorylates eIF2 to inactivate eIF2alpha to inhibit protein synthesis in a localised manner.
14
Q
What are some examples of ISGs?
A
OAS, RNAse L, PKR
Mx proteins - inhibit viral molecular movement
dsRNA specific adenosine deaminase (A->inosine in dsRNA)
miRNAs
Intrinsic factors unregulated
Pro inflammatory cytokines eg. TNFalpha
Induce adaptive immunity
15
Q
How do IFNs induce adaptive immunity?
A
Skew Th1
License dendritic cells
Activate NK cell killing
Give resistance to T cells against NK cell killing
16
Q
What are type 2 interferons?
A
IFNgamma. Produced by T lymphocytes (CD8 and some CD4 e.g. Th1) and NK cells. Binds type II receptor. Induces expression of some ISGs (like type 1 - overlap). Lower antiviral activity than type 1 IFN. Induces an inflammatory response (Th1) and is very important for controlling systemic infections.
17
Q
What does IFNgamma do?
A
Increases MHC I expression on macrophages, DC and endo/epithelial cells
Induces MHC II expression on some MHC II negative cells
Increases expression of immunoproteasome components and TAP for MHC cleavage
Promotes cell mediated immunity
18
Q
How does IFNgamma promote cell mediated immunity?
A
Antagonist of IL-4 and IL-10 to encourage development of Th1 cells
Induces chemoattractants
Activates macrophages
Works with TNFalpha
19
Q
What is the role of IFNgamma in defence against viruses?
A
Aids development of anti-viral immunity
Important in viral clearance - essential for vaccinia virus clearance
20
Q
What do type 3 interferons do?
A
IFNlambda1,2,3. Expression is induced by PRRs, signal through JAK/STAT pathway. Unregulate similar genes to type 1 IFNs and increase MHC 1 expression. Target specific cells as expression of the receptor is not ubiquitous. Important in defending against flu (one of the target cells is epithelial cells)
21
Q
What does TNFalpha do?
A
Produced by monocytes and macrophages (major) as well as CD8 T cells, NK cells and DC (minor). Can be membrane bound or soluble. Interaction with TNF-R1 induces apoptosis and inflammation. Localised expression is important for virus clearance.
Kills virally infected cells (apoptosis induction)
Induces expression of OAS and IFNbeta
Controls the inflammatory response
Works with IFN gamma and beta
22
Q
How does the immune system detect viral RNA?
A
RIG-I like receptors such as RIG-I, MDA5. Bind ssRNA (RIG-I) and dsRNA (MDA5) in the cytosol by their helices domain. Induces IRF-3 or NFkB.
23
Q
How does the immune system detect viral DNA?
A
DAI binds dsDNA in the cytosol along with other sensors. Cause inflammation
24
Q
What are inflammasomes?
A
Complexes of NOD-like receptors/AIM2(a dsDNA receptor) with ASC and caspase-1. Cleaves proIL-1beta to IL-1beta.
25
What PRRs exist on the cell surface?
TLR4 - RSV detection
| TLR2 - measles HA and HCMV gB
26
What PRRs exist in endosomes?
TLR7/8 - U/G rich ssRNA (flu, HIV)
TLR9 - unmethylated CpG DNA (HSV)
TLR3 - dsRNA
All induce NFkB and IRF3
27
How do neutralising antibodies work?
Antibody sterically hinders viral functions such as receptor binding, penetration and uncoating
Antibody could also denature the virion structure causing loss of infectivity/inhibiting or inducing change in virion structure so it can't function
28
What is ADCC?
Antibody dependent cellular cytotoxicity. Focuses NK cells and macrophages to infected cells for killing/phagocytosis. Gives antigen specificity to non-specific effector cellls
29
What are the mechanisms of function of antibody against viruses?
```
Neutralisation
Antibody dependent cytotoxicity
Agglutination of virus particles
Opsonisation of viruses and infected cells
Interacts with complement
```
30
How can viruses evade antibody function?
Antigenic shift/drift
Expression of FcRs to sequester antibody
Antibody mediated enhancement
31
How is a T cell response triggered?
Naive T cells are exposed to antigen in the lymph node when they come into contact with an APC. Activated and leave for site of infection.
32
What do cytotoxic T lymphocytes do?
CD8 T lymphocytes - class I MHC restricted. Eliminate virus infected cells. Are activated in the lymphoid tissue, go to target tissue where there are many functions including killing.
33
How are CD8 T cells activated?
Dendritic cells must be licensed. CD40 on DC interacts with CD40L on T cell, along with MHC I + TCR interaction.
For T cell expansion, require inflammatory cytokines such as IL-12, IL-2 and type I interferons
34
What is CTL exhaustion?
If the virus replicates too quickly or there is a very high viral load, the T cell response is poor and the virus can persist.
35
What is the importance of CTLs in viral clearance?
Very important for clearance LCMV in mice
| Though some viruses can be cleared without CTLs e.g. flu
36
How do CTLs kill target cells?
Contain lytic granolas - engagement of TCR causes pseudopod formation and movement of granules to site of contact. Granules are exocytosed next to target cells.
Fas signalling - signalling though FADD and caspase 8 to induce apoptosis
37
What are contained within T cell lytic granules?
Perforin - calcium dependent polymerisation to form a pore in the membrane (similar to C9). Suggested to allow entry of granzymes into the cell through membrane repair (endosomes)
Granzymes - granule serine proteases A, B + others. Granzyme B activates caspase 3 (leading to apoptosis). Granzyme A activates apoptosis without caspases - mitochondrial and ssDNA damage.
Both are protein synthesis independent
38
What cytokines do CTLs produce?
IFNgamma and TNFalpha
| Also makes some chemokine that inhibit HIV replication by blocking the cellular receptors
39
What are CTL escape mutants?
If the CTL response is skewed towards one or two immunodominant epitopes and the viral load is high enough, some virus may evolve to escape the CTL response. Seen in HIV disease progression
Mutation of the dominant epitope causes loss of stimulation of the dominant specific T cells and allows stimulation of subdominant epitopes
40
How can CTL activity be measured?
Measuring target cell death
Measuring cytokine production (ELISA - incubate cells on plate with anti-cytokine, wash off cells, add more antibody conjugated to an enzyme)
Measuring cytokine staining with flow cytometry
MHC class I staining - express MHC I with a biotin tag and a specific peptide in E. Coli, stain for antigen specifity of the T cell (shows most T cells are virus specific)
41
How do CD4 T cells defend against viruses?
Cytokine production - can stimulate the inflammatory response (Th1 i.e. IFNgamma)
Help B cells and CD8 T cells
In mice, get protective CD4 T cells against flu - express IFNgamma which induces expression of MHC class II to aid virus clearance.
42
How are memory T cells induced and maintained?
Need IL-7 or IL-5 (CD4 vs CD8). For establishing a stable pool of memory CD8 T cells need CD4 help.
43
What are the different types of memory CD8 T cells
Central memory - proliferate to antigen and differentiate for effector function
Effector memory - don't proliferate to antigen, get an effector function on antigen stimulation
Effector CTLs
Tissue resident memory T cells
44
How do herpes viruses hide from the immune system?
Herpesviruses - latent/persistent infections, some can integrate into telomeric regions of the chromosomes
45
How do retroviruses hide from the immune system?
Retroviruses - integrate into the genome and is quiescent (not replicating) if not near a promoter. Also 2 stages of error prone transcription (reverse transcriptase and host polymerase transcription)
46
How does HSV and VZV evade the immune system?
Immunoprovileged sites - e.g. nervous system where there are low levels of MHC class I. E.g. HSV and VZV in neurons
47
How does HBV and HCV evade the immune system?
Immunoprovileged sites - e.g. liver where there are low levels of MHC class I. E.g. HBV and HCV infect liver
48
How does LCMV evade the immune system?
Inducing tolerance - e.g. LCMV in mice. No disease in naive newborn but will kill naive adult mouse
49
How can viruses evade antibody?
Spread from cell to cell (no exposed)
Spread through tight junctions (antibody restricted due to space)
Spread through neural junctions
Actin tails to drive virus from one cell to the next
Virological synapse (e.g. HTLV)
Spread from host to host in infected cells (e.g. HIV)
Evade Fc
Mask antibody binding sites
50
How can viruses evade Fc?
Express their own Fc receptor/a protein that binds Fc so Fc receptors are blocked and the virus isn't phagocytosed
51
How does Dengue virus evade antibody response?
Antibody response to a different serotype makes the infection more dangerous - the antibodies bind but don't neutralise the virus. The virus then uses host Fc receptors to infect cells more quickly
52
How does HIV mask antibody binding sites?
Has a glycan shield on gp120 to make it more difficult to produce antibody against it
53
How do RNA viruses evade drugs and the immune system?
Error prone polymerase. Retroviruses are doubly error prone as they have 2 polymerases that are error prone. Large range of quasi-species aiding the fight against drugs and the immune system. However, the error prone nature limits the size of the the virus genome - largest RNA viruses have proof reading capacity
54
How does influenza do antigenic shift?
Re-assortment of segmented genomes when two viruses co-infect the same cell. E.g. could have a human and avian virus in the same cell, get most coding segments from human but HA from avian. Means there is no immunity against the virus at all but it is well adapted to human cells.
55
What is the structure of A49 in poxviruses?
Small, low pI, conserved in many poxviruses (but not all so not essential for replication). Where present is highly conserved with a completely conserved amino box at the N terminus
56
What do intracellular genes that evade immunity in VACV do?
Virus makes steroids which are immunosuppressive (e.g. glucocorticoids) as well as inhibiting apoptosis, signalling pathways, interferon-induced antiviral proteins or cytokine maturation
57
What do extracellular genes that evade immunity in VACV do?
Bind and neutralise/stop binding to receptors of cytokines, chemokine, interferons, complement
58
What do cell surface genes that evade immunity in VACV do?
Influence how the cell is recognised by NK cells or CTLs and same as extracellular
59
How do viruses evade complement?
Viruses evolve complement control proteins - likely acquired from the host genome which are expressed on the virus/infected cell surface
Virus steal complement control proteins as it buds from the infected cells - works even if virus crosses species
gC of HSV binds C3b
Soluble inhibitors of complements e.g. BVP binds C3b and C4b to block activation cascades in VACV infection
60
What is the effect of deleting A49 in VACV?
In vitro - no difference in plaques
In vivo (mice weight loss system) - less weight loss and fewer signs of illness. Also less virus in the lungs
Suggests it is a virulence factor
61
How was the link between A49 and NFkB made?
Reporter gene assay - link NFkB promoter to luciferase. When A49 transfected in, got less luciferase production ni a dose dependent manner. This worked when the cells was challenged with both IL-1 and TNFalpha, suggesting that the effect was after the pathways converge - at the IKK complex.
62
How was the point in the NFkB pathway that A49 acted discovered?
Over expressed different parts of the pathway and work to see what rescued it. Found that over expression of p65 rescued, suggesting A49 worked around IkB. Sequence analysis showed a similar sequence to IkB on A49 - could be acting as a mimic.
63
What is the sequence similarity between IkB and A49?
IkBa has a motif with two series with two lysine upstream where ubiquitin is added (IkB is then degraded by beta-TrCP to release NFkB)
A49 has two serine motifs but no upstream lysine.
64
How did pulldown experiments inform the action of A49?
Found that A49 pulled down with the WD40 domain of the ubiquitin ligase beta-TrCP. Found that mutating residues that are phosphorylated by IKK stops pulldown and NFkB inhibition, whilst mutating to an E (that mimics phosphorylation) increases pulldown.
Suggests that A49 binds a ubiquitin ligase, possibly preventing it from acting on IkB
65
What is the function of A49 in VACV?
It inhibits the NFkB pathway by interacting with the beta-TrCP ubiquitin ligase to prevent degradation of IkB when it has been phosphorylated by IKK - so only works when the NFkB pathway is active
Also has another function, as mutating the phosphorylation residues to E (mimicking constitutive phosphorylation) still leads to a decrease in virulence, suggesting that constitutive binding prevents the protein doing other things.
66
How are proteins presented on MHC class I?
Endogenous proteins are degraded, then go through TAP (transporter in ER) and loaded onto MHC I in the lumen of the ER. This is translocated to the cell surface
67
How can viruses interfere with the MHC class I pathway?
```
Prevent generation of peptides
Inhibit peptide transport
Destabilise MHC so can't load peptides
Inhibit MHC transport
Remove MHC from the cell surface
```
68
How can viruses prevent the generation of peptides of MHC class I?
Inhibit the proteasome
| EBV EBNA1 protein - has glycine and alanine repeats that makes it resistent to degradation and inhibits the proteasome
69
How can viruses prevent peptide transport in the MHC class I pathway?
TAP inhibition
ICP47 (herpes) binds TAP and prevents loading and transportation
US6 does the same thing at a different binding point
70
How can MHC class I be destabilised by viruses?
E3 ligases can ubiquitinate MHC class I causing their degradation by the proteasome. E.g. MHV 68 mK3
71
How can MHC class 1 transport be inhibited?
Signal sequences on a viral protein acting as a tether e.g. adnavirus E3-19K
72
How can MHC class I be removed from the cell surface?
E3 ligase activity - kK3 from KSHV ubiquitinylates the cytoplasmic tail, causing MHC internalisation by endocytosis and degradation in the lysosome
73
How can virus pathways that interfere with MHC class I be exploited?
Removing these virus inhibitors could make a good vaccine - would be more immunogenic than normal as the virus would be presented properly, and the virus would be attenuated.
74
How are proteins presented on MHC class I?
Endogenous proteins are degraded, then go through TAP (transporter in ER) and loaded onto MHC I in the lumen of the ER. This is translocated to the cell surface
75
How can viruses interfere with the MHC class I pathway?
```
Prevent generation of peptides
Inhibit peptide transport
Destabilise MHC so can't load peptides
Inhibit MHC transport
Remove MHC from the cell surface
```
76
How can viruses prevent the generation of peptides of MHC class I?
Inhibit the proteasome
| EBV EBNA1 protein - has glycine and alanine repeats that makes it resistent to degradation and inhibits the proteasome
77
How can viruses prevent peptide transport in the MHC class I pathway?
TAP inhibition
ICP47 (herpes) binds TAP and prevents loading and transportation
US6 does the same thing at a different binding point
78
How can MHC class I be destabilised by viruses?
E3 ligases can ubiquitinate MHC class I causing their degradation by the proteasome. E.g. MHV 68 mK3
79
How can MHC class 1 transport be inhibited?
Signal sequences on a viral protein acting as a tether e.g. adnavirus E3-19K
80
How can MHC class I be removed from the cell surface?
E3 ligase activity - kK3 from KSHV ubiquitinylates the cytoplasmic tail, causing MHC internalisation by endocytosis and degradation in the lysosome
81
How can virus pathways that interfere with MHC class I be exploited?
Removing these virus inhibitors could make a good vaccine - would be more immunogenic than normal as the virus would be presented properly, and the virus would be attenuated.
82
What evidence is there for antigen specificity of NK cells?
Mainly in an antigen independent manner, but do show evidence of some immunological memory - challenging an animal with a virus, purifying the NK cells, giving to another animal and challenging gives the second animal an advantage.
83
How do viruses evade NK cells?
```
Viral MHC class I molecules expressed to give inhibitory signal
Regulate expression of MHC class I levels - down regulate specific types
Inhibit activating receptor function
Express ligands for inhibitory receptors
```
84
How do viruses regulate MHC class I levels?
Often down regulate specific types of MHC - HLA A/B present to CTLs, so these are down regulated, whilst HLA C/E are retained which still provide an inhibitory signal to NK cells
KSHV k5 retains HLA C
HIV nef retains HLA C/E
MCMV UL40 enhances HLA E
85
How do viruses inhibit the activating receptor of NK cells?
HCMV UL16 binds ULBPs, ligands for NKG2D and blocks activation
KSHV k5 down regulates MICA and MICB - activating ligands
86
How do viruses induce inhibition of NK cells?
Expressing ligands for inhibitory receptors
| Orthopoxviruses express a soluble protein that binds NKG2D
87
What is the effect of deleting F12 from poxviruses?
F12 is required for large plaques
When infecting viruses with F12 deletion into mice, there is no weight change no matter the dosage - fast spread is required for virulence
88
How do pox viruses spread on a plate?
Wester reserve - get a primary and a secondary plaque in a medium which allows particle diffusion (only primary in a semi-solid overlay)
IHD-J - get comet shaped plaques (EEV release in a unidirectional manner due to convection currents). If add an antibody to EEV, comets are lost, but the size of plaque is retained, so virus can spread in an antibody resistant way.
89
What did the plaque assay tell us about the replication kinetics of poxviruses?
By looking at plaque size and number of cells infected, can work out how long VACV takes to move between cells. Found a time of 1.2hrs but it takes 6hrs for a cell to make the first virus particle. This was done in a semisolid medium so movement is not by diffusion
90
How do poxviruses use actin tails to spread? How was this discovered?
GFP fused to a late capsid protein in the virus; stain cells with DAPI so can see virus replication sites. See some green particles associated with red actin, but no green cell (virus not made yet).
Stain some cells red for actin, and don't stain others, mix. Look at red/wt boundary and look for red cells with green particles. Observe that actin and viruses come from different cells
Actin tails can push away virus from cells. Suggests a virus protein pushes super infecting virions away
91
How were the poxvirus proteins that aid virus spread by induction of actin tails identified?
Candidate proteins were those that were expressed early and late in infection, but the early function was unknown. Included A33, A36 and B5.
Engineered viruses to only have late promoter and observe effect on plaque size - A33 and A36 significantly reduced.
A33 and A36 are sufficient to form actin tails - transfect cells with A33 and A36, viruses still bounce.
92
What is the model for poxvirus rapid replication kinetics?
In cell 1 virus undergoes a full cycle of replication. Virus is released on actin tails and infects neighbouring cells. A33 and A36 are expressed as a complex which induces actin tails to push super infecting virions away. Get rapid infection by bouncing visions to uninfected cells
93
What are interferons?
Species specific glycoproteins that are induced upon infection (and other). Trigger an antiviral state and help activate the innate immune system. Lack of interferon results in susceptibility to infection and a poor memory response
Viruses encoding interferon are avirulent, and treatment of cells/animals with interferon before infection helps contain the infection. Most viruses have an interferon inhibitor, some have many
94
How do viruses interfere with type 1 interferons?
```
Can block PAMP recognition
Block IRF3/NFkB signalling
Stop transcription or production of IFNalpha/beta
Block IFNa/b binding or soak up IFNa/b
Block JAK/STAT signalling
Block transcription from ISRE promoters
Block action of ISGs
```
95
How do viruses block PAMP recognition?
Bind dsRNA to hide it (e.g. E3 in VACV)
| Bind RNA sensors (paramyxovirus V proteins binde MDA-5; Influenza NS1 binds RIG-I)
96
How can viruses stop transcription or production of type 1 interferons?
Shut down host protein synthesis e.g. polio
97
How can viruses block interferon binding?
B18 and B8 in VACV:
B18 is soluble and binds type 1 interferons - it is a mimic of the interferon receptor.
B8 does the same for type II interferons.
98
What does B18 of VACV do?
B18 is soluble and binds type 1 interferons - it is a mimic of the interferon receptor. It can also bind to cell surfaces so interferons are captured in solution and on cells surface - neighbouring cells are not in an antiviral state. Evidence from plaque assay in cells treated with interferon before infection with wt/deletion mutants
99
What does B8 of VACV do?
B8 is soluble and binds type II interferons. Has 21% identity to the extracellular domain of the receptor - potentially 'stolen' from the host and lost the transmembrane domain through evolution. Is expressed early and binds IFNs from many species to aid zoonotic infection
100
How can viruses block JAK/STAT signalling?
Phosphatase in VACV VH1 (is present in the virion) dephosphorylates STATs
Simian virus 5 V protein degrades STATs
101
How can viruses block transcription from ISRE promoters?
VACV protein C6 induces degradation of cellular proteins - some weren't known to be involved in interferon signalling. Virus has informed us.
102
How can viruses block action of ISGs?
HCV NS5A binds PKR
| HIV induces expression of an RNAse L inhibitor
103
How have viruses informed us about our own physiology?
Control of body temperature by IL-1beta from study of VACV protein B15
Finding DNA PRRs
Many others
104
What is the structure of VACV protein B15?
Predicted to have glycosylation sites, has 20-25% homology with IL-1 receptor. Suggested to be adapted IL-1 receptor to be secreted and bind IL-1. Found that it only bound IL-1beta - not IL-1alpha or negative regulators, and is secreted in high quantities so is an effective competitor. Isn't essential for replication as not all VACV make it
105
How has the study of VACV protein B15 informed us about our own physiology?
Is secreted and binds IL-1beta; not essential for replication. When wt and a deletion mutant were infected in mice, found that wt mice didn't get a fever, but deletion mutant viruses did. From this, found that IL-1beta is important for temperature control
106
What was the experiment done to try and find DNA PRRs?
DNA was biotinylated and put into cells. After 1hr, DNA was extracted using the tag and proteins bound were examined. They were abundant - seen from a coomassie stain. Using mass spec and antibodies, large amounts of DNA-PKcs and Ku80 and Ku70 were found, along with weak amounts of PDH2
107
What is the function of DNA-PK?
DNA protein kinase bind cytoplasmic dsDNA. Is known to be required in DNA repair and V(D)J (non-homologous end joining). Triggers the immune response through IRF3. Is a sentinel receptor - high endogenous levels in cells likely to be infected first (e.g. fibroblasts). VACV sensing requires DNA-PK
108
What is the function of PHD2?
An oxygen sensor - hydroxylates HIF1a in the presence of oxygen, triggering degradation of HIF1a. When hypoxic, it can't hydroxylate HIF1a. It moves to the nucleus and forms transcriptional complexes for HIF response element containing genes.
Virus binding to PHD2 results in a hypoxic response in normal oxygen levels. Thought to have linked to metabolism and the immune system.
109
How do poxviruses interfere with DNA-PK signalling?
```
Protein C16 (and C4). Interacts with Ku via the C terminal domain but not DNA-PK. Inhibits the binding of Ku70/80 and DNA-PKcs to DNA. This reduces IRF-3 signalling and therefore production of IFN, chemokines and cytokines.
Found in VACV and VARV but MVA (attenuated version of small pox) C16 has a deletion (5aa in C terminus) so isn't functional in this capacity.
```
110
What is the function of vaccinia virus protein C16?
Expressed early in infection, not necessary for replication in cell culture, deletion mutants attenuated in mouse intranasal model with increased cytokine and inflammatory cell responses. Has homology to VACV protein C4. Also binds PHD2 to prevent the cell inducing a hypoxic state.
111
What different types of infection timelines can viruses employ to ensure survival against the immune system?
Acute virus infections - virus is transmitted before the infection is eliminated. Requires rapid replication and transmission or extra host survival (e.g. infecting more than one species or hardy virions)
Persistent virus infections - virus is sufficiently non-cytopathic so the host survives and avoids clearance by the host antiviral immune system (esp. cell mediated immune response)
112
How can persistent viruses ensure their replication is tolerated by the host?
Non-lytic productive infection (e.g. LCMV and HBV)
Evolve less cytolytic viral variants (e.g. from a zoonotic infection)
Infect non-permissive cell types (e.g. herpesviruses, papillomaviruses)
Lytically infect a renewable cell type (e.g. LDHV infects macrophages)
