viral evasion strategies - virology blogviral evasion strategies lecture 15 virology w3310/4310...
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Viral Evasion Strategies
Lecture 15Virology W3310/4310
Spring 2013
“Don’t look back, something might be gaining on you!”-SATCHEL PAIGE
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Host vs. Virus
• What one does to the other?
• Evolution of strategies to evade innate and adaptive cell responses to infection - goal: survival, reproduction and release
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Strategies for Evasion
• Overwhelm the host
• Enter parenterally - Anyway other than the gut - Why?
• Disarm host defenses
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Acute Infections
SymptomsWhen to treat?
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Virus Offense Meets Host Defense
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Evasion• VIPRS - viral proteins that interfere with
antigen presentation
• Disarm innate immunity
• Regulate MHC molecules - responsible for antigen presentation
• Alter antigen presentation
• Interfere with CTL and NK cells
• Go and hide More on this later
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Host Defenses• Innate immunity, responds to everything
• Intranuclear modulatory molecules
• Immune system, recognizes signal, amplifies signal and controls invader
• Interferons induce an antiviral state PKR
• Complement punches holes in membranes
• NK and CTLs
• Macrophages and neutrophils7
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Adaptive Immunity
• A memory response
• Activated in response to the innate immune system
• Results in clonal expansion of B and T cells - requires CD4+ Th1 and Th2 cells
• Generation of Cytotoxic T celLs and antibody production
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Inflammatory Response
• Occurs in response to necrosis
• Results in release of cytokines and chemokines
• Recruits neutrophils and macrophages to site of damage
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Cytokines
• Primary output of innate immune response
• Rapid induction in response to infection
• Control inflammation
• Induce antiviral state, IFNs
• Regulate immune system
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Viral Response
• Virokines, it looks like, smells like, so don’t step in it - these mimetics bind and sequester host receptor molecules
• Viroceptors - soluble cytokine receptors - divert cytokines from initiating response
• Sabotage innate and adaptive defense without affecting growth in cell culture
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Products that Counter IFN
• Why? - Without IFN host has a reduced ability to contain viral infections
• dsRNA binding proteins - NS1 from Influenza - E3h from Poxviruses - US11 from HSV
• Ad VA-RNA - A dsRNA decoy that binds PKR
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Modulators of the IFN Response
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Regulators of ISGs
• ND10s are composed of host proteins that repress virus replication - innate nuclear defense - epigenetic regulation of virus replication - PML, an important ND10 constituent
• Some Herpesviruses targets PML for proteolysis
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Dissolution of PML
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Translational Regulation
• Viruses modify host to favor synthesis of their own proteins
• IFNs establish an anti-viral state
• Induction of Protein Kinase R and other eIF2α kinases - inhibit translation - consequences for virus replication
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Innate Defense Targets
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PKR
• Activated by binding dsRNA
• Autophosphorylates at S51
• Phosphorylates eIF2α - forms a very tight ternary complex with GDP- eIF2B - blocks recycling - translation is arrested
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How Viruses Counteract Pkr
• Virus proteins have evolved to thwart host anti-virus defenses
• HSV US11 blocks Pkr activation by binding to it
• Adenovirus VA RNAs bind tightly to Pkr - dsRNA decoy
• HPV E6 and HSV γ34.5 dephosphorylate eIF2α - γ34.5 interacts with PP1a redirecting it to eIF2α
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Phosphorylation of eIF2α
HSV US11Ad VA RNAs
HPV E6HSV γ34.5
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Viral Modulators of Interferon
• Inhibit IFN synthesis
• IFN Receptor decoys
• Inhibition of IFN signaling
• Inhibit Interferon Stimulated Genes
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Autophagy
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For example, the most commonly used autophagy assays, biochemical detection of the lipidated form of LC3 (LC3-II) and detec-tion of the localization of LC3-II to punctate dots by light microscopy, are subject to many interpretations. Most investigators now rec-ognize that detection of increased LC3-II can indicate either more autophagosome forma-tion or a block in autophagosomal matura-tion, which necessitates the use of ancillary approaches to distinguish between these possibilities14. Perhaps less well appreciated is the idea that LC3 dots may represent the targeting of LC3 to structures other than autophagosomes, such as phagosomes, dou-ble-membraned scaffolds for the replication complexes of positive-strand RNA viruses, or even protein aggregates15–17. Similarly, LC3 may become lipidated, forming LC3-II, in the absence of autophagosome formation18,19. Thus, whereas LC3-II formation and localiza-tion of LC3 punctae are hallmark features of autophagosome formation (and sensitive parameters for the detection of autophagy), they lack complete specificity as markers of classical autophagy. The direct demonstra-tion of a function for autophagosomes in a process is the gold standard for proving that autophagy is involved. An extensive discus-sion of the various assays used in autophagy research, as well as the criteria for their use and interpretation, has been provided in a consen-sus paper published by many of the authorities in the field14.
The genetic knockout or knockdown of core autophagy genes is an effective way to turn off the autophagy pathway, but it is often unclear whether resulting phenotypes are due to a deficiency of classical autophagy or autophagy-independent functions of the autophagy genes. As reviewed elsewhere, autophagy genes are known to have alternative functions, including those in other membrane-trafficking events, axonal elongation and cell death20,21. Furthermore, investigators often assume that phenotypes noted in autophagy gene–deficient cells or organisms are due to lack of classical autophagy without providing direct experi-mental proof. Notably, for many studies of the involvement of autophagy genes in immunity (Fig. 3), it is not clear how classical autophagy, involv-ing the autophagolysosomal degradation of sequestered contents, could contribute to the described functions of autophagy genes. Thus, it is possible that autophagy genes act in other cellular processes that affect immune effector cell development and function. Here we will discuss advances related to the function of autophagy genes in the immune system.
Autophagy genes in antimicrobial defenseMore than a decade ago, the first published paper on Beclin 1, a mam-malian autophagy protein, demonstrated an antiviral function for exogenous neuronal expression of Beclin 1 in mice with alphavirus encephalitis22. Subsequently, endogenous autophagy genes were shown to be critical for the successful innate immune response to fungal, bacte-rial and viral pathogens in plants23, and viral evasion of Beclin 1 function by a herpes simplex virus neurovirulence factor was found to be essential
for lethal encephalitis in mice24. These studies collectively suggested a likely function for autophagy genes in pathogen defense in vivo. In parallel, many studies demonstrated a function for autophagy in vitro in defense against invading pathogens, including group A Streptococcus, Shigella flexneri, Mycobacterium tuberculosis, Salmonella typhimurium and Toxoplasma gondii10,11,13.
Two recent studies have further confirmed an antimicrobial func-tion for autophagy genes in host defense in vivo against intracellular pathogens and have identified previously unknown relationships among innate immune signaling, autophagy genes and potential autophagy-independent functions of autophagy genes. An innate microbial sensor, the peptidoglycan-recognition protein PRGP-LE, which recognizes bac-terial diaminopimelic acid–type peptidoglycan, is crucial for autophagic control of Listeria monocytogenes infection in fly hemocytes and for host survival25. PRGP-LE-mediated resistance is associated with autophagy induction, requires the autophagy gene Atg5 and presumably involves the xenophagic degradation of bacteria (as bacteria are visualized in autophagosomes in wild-type animals). In this case, xenophagy tar-gets cytoplasmic bacteria that have escaped from the endosome for envelopment in an autophagosome and destruction. In other cases in which a pathogen inside a vesicular structure is targeted (such as mycobacteria inside phagosomes, or salmonella inside vacuoles), the membrane dynamics involved are incompletely defined. It may be that an autophagosome can envelop the entire vesicular structure containing
462 VOLUME 10 NUMBER 5 MAY 2009 NATURE IMMUNOLOGY
AUTOPHAGY
Vesiclenucleation
Isolationmembrane
Vesicleelongation
Vesicle breakdown& degradation
Autolysosome
Lysosome
Autophagosome
Docking &fusion
Atg5
Atg16L1
Atg16L1
Atg16L1
Atg16L1
Atg12
Atg16L1
LC3
Atg10 E2Atg5
Atg12
Atg5
Atg12
Atg5
Atg12
Atg5 Atg12
Atg5
Atg12
Atg4
LC3 -GlyAtg3 E2
LC3PE
LC3
Atg7 E1
Beclin 1
Class III PI(3)K complex
Vps34
Vps15Atg14
Bcl-2–Bcl-XL
Otherregulators
Ubiquitin-like conjugation systems
P
Autophagy suppression
Nutrient abundance
Insulin-Akt-TOR signaling
Immune signals:
IL-4
IL-13
FADD
Immunity-related GTPases
Autophagy induction
Starvation
Growth factor deprivation
Immune signals:
IFN-
TNF
TLRs
PKR-elF2 kinase
Jnk
FADD
Immunity-related GTPases
Figure 1 The autophagy pathway and its regulation. The autophagy pathway proceeds through a series of stages, including nucleation of the autophagic vesicle, elongation and closure of the autophagosome membrane to envelop cytoplasmic constituents, docking of the autophagosome with the lysosome, and degradation of the cytoplasmic material inside the autophagosome. Vesicle nucleation depends on a class III PI(3)K complex that contains various proteins (in light yellow box at right), as well as additional proteins that regulate the activity of this complex (such as rubicon, UVRAG, Ambra-1 and Bif-1). Vesicle elongation and completion involves the activity of two ubiquitin-like conjugation systems (light blue box at right). The autophagy pathway is positively regulated (green box at left) and negatively regulated (red box at left) by diverse environmental and immunological signals. TNF, tumor necrosis factor; PE, phosphatidylethanolamine; Gly, glycine; E1 and E2, ligases for ubiquitin-like conjugation systems.
REV IE Wa catabolic process involving degradation of a cell's own
components through the lysosomal machinery
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Stimulation and Inhibition of Autophagosome Formation
Mock HCMV UV-HCMV
4 h
8 h
24 h
LC3 an autophagy marker
pp65 HCMV protein
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How Does HCMV TRS1 Work?
• TRS1 Binds PKR and ds RNA Innate immune response is inhibited
• Interacts with and sequesters Beclin Inhibits autophagy
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ds RNA Binding Domain
PKR Binding Domain
TRS1 (1-795)
Beclin Binding Domain
TRS1 an Inhibitor
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• Host escape mechanism leading to cell death and inflammation by cysteine proteases (Caspases) - induction of cytokines - infected cells release proteins that are subsequently presented by MHCII - activation of CTLs
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Apoptosis
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Apoptosis
• Catabolic process involving degradation of a cell's own components through the lysosomal machinery
• Host controls induction and suppression
• Antiapoptotic:BCL-2 family members block mitochondrial translocation
• Proapoptotic:BAX and BAD cause induction of a caspase cascade by release of mitochondrial cytochrome C
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Characteristics of Apoptosis
• Cell organelles are dismantled
• Vesicle formation and membrane blebbing
• DNA is cleaved
• Phosphatidylserine, annexin appear on cell surfaces
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Apoptosis
• Perturb the cell cycle and apoptosis is activated - cell falls apart and virus fails to complete replication cycle
• Block it and virus can complete replication
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Characteristics of Apoptosis
• Membrane blebbing and apoptotic body formation
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Characteristics of Apoptosis
• HSV ICP27 prevents DNA fragmentation
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Why Block Apoptosis?
• Why are cells induced after infection? - activation of quiescent cell machinery - checkpoint controls respond
• Virus responds to complete replication - failure leads to decreased yields
• Inhibit release of virus Antigens - eliminate T cell activation - evade immune response
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How to Block It
• HCMV transcribes a noncoding RNA (β2.7) that binds a mitochondrial protein that triggers apoptosis
• AD E1B binds BAX preventing caspase activation (intrinsic)
• AD E3 blocks Fas (Death Receptor) - induced apoptosis (extrinsic)
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HIV Evades the Rig I Innate Immune Response
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HIV Sequesters RIG-I to Lysosomes Where It Is Degraded
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GFP-Protease+
Saquinavir
GFP-Protease RIG-I LAMP-1 Merge
GFP-Protease
GFP RIG-I Cytoplasmic
RIG-I Perinuclear
RIG-I Perinuclear
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Apobec
• A protein family whose function is to edit RNA - an ISG - deaminates C U
• Intrinsic antiviral
• Blocks replication of HIV, HBV and Measles
• Incorporated into HIV virus particles - Is the host a step ahead here?
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How Apobec Inhibits HIV Replication
• C’s in - strand DNA are deaminated
• C U transitions result in GC AT pairs - TGG (W) codons become TAA (Stop)
• U containing DNA is attacked by U-DNA glycosidase - generates abasic site and becomes a target for endonucleases
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• HIV encodes Vif which is incorporated in the virion
• Vif interacts in a species specific manner to bind Apobec and target it to the proteasome
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How HIV Survives Apobec
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Humoral & Cell Immunity
MHC II MHC I
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Two signal systems, MHC and accessory molecules and their ligands - lead to T cell activation
T Cell Surface Molecules and Ligands
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Th2 Th1
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Effects of Stimulating Cell Division• Clonal expansion - increases # of cell responders
• T cells kill cells bearing foreign peptide or protein - CD4+ Th recognize MHC II bound peptides - CD8+ Tc recognize MHC I bound peptides
• In response to cytokines from Th1 cells CD8+ become mature CTLs
• In response to cytokines from Th2 cells B cell synthesizes Ab (becomes a plasma cell)
• B cell can also become a memory cell43
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Adaptive Immunity
• Humoral
• Cell-mediated, recognition mediated by: - membrane bound Ab on B cells and/or TCR - Ag presented by MHC I on all cells - Ag presented by MHC II on macrophages or dendritic cells
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Immune Modulation
• Dendritic cells are often compromised by virus infection resulting in suppression of the immune response by: - interference with recruitment - impairment of Ag uptake or processing - interference with maturation - inability to migrate to lymphoid tissue - failure to activate T cells
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Remediation of T Cell Response
• EBV encodes an IL 10 homologue that suppresses the Th1 response
• KSHV elaborates a horde of virokines (cytokine mimetics) that provide a refuge from immune surveillance
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• No antigen receptors
• Secrete cytokines
• Kill cells lacking MHC I on the surface by recognizing missing self
• ADCC, NKs bind to IgG coated cells, release perforins and granzymes triggering apoptosis
Natural Killer Cells
IR>>AR
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I
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Virus Modulation of NK Cells
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1-Mimetic
2-Downregulation & substitution
3-Block activating proteins
4-Inhibition of NK-stimulating cytokines or antagonist of activating chemokines
5-Block receptor or kill cell
antagonist
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Virus Modulation of NK Cells
• MHC I homologs
• Regulators of MHC I
• Release of Viroceptors block engagement of activating receptor
• Antagonist (Virokine) of activating receptor
• Infection of NK cell can lead to disruption of function or cell death
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Virus Modulation of NK Cells
• HCV E2 protein binds CD81 on NK cells to block activation - don’t recognize infected cells
• HIV nef affects cell surface expression of some MHC I molecules but not HLA-E (cell is still protected)
• Poxviruses express proteins that bind IL-12 to inhibit IFN-γ production by NKs
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Exogenous Antigen Presentation
post-Golgi vesicle
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MHC I Presentation
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Fine Structure of MHC I Presentation
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• Viral proteins interfere with MHC I mediated antigen presentation
• Just how many targets are there?
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Intercession of TAP Transport
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X ATP-bindingX peptide-binding X ATP & Peptide-binding
HSV HCMV EBV
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Intercession with Tapasin
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X Blocks MHC I Tapasin Interaction Preventing
Peptide Loading
X Interacts with Tapasin Resulting in MHC I Degradation
Adeno HCMV
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Cytomegaloviruses a Paradigm for Interference with MHC
• UL83 tegument protein inhibits proteasome processing by P*
• US6 inhibits MHC I translocation to the ER
• US3 inhibits MHC I transport across ER
• US2 & 11 force MHC I to cytoplasm
• UL18 is a MHC I mimetic thought to downregulate NK and CTLs
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MHC Intercession Summary
• Viruses have to cope with their hosts
• For the host to succeed viral antigens must be presented on the cell surface
• Viruses have identified many points of intercession and defined how MHC I presents antigen
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• Secreted Modulators
• Modulators on infected cell surface
• Stealth
• Antigenic hypervariability
• Bypass or kill lymphocytes
• Block adaptive immune response
• Inhibit complement
• Modulate apoptosis
• Modulate autophagy
• Interfere with pattern recognition receptors
Immune Modulation Strategies
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