Transcript 03-Chapter-8-supplement

Viral Evasion Strategies
Supplement to Chapter 8
Finlay and McFadden. 2006. Cell. 124:767-782
Viral Evasion
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Viral evasion is the use of virus-encoded proteins that
disable or modulate the immune response in favor of
the virus
Most medium to large viruses (8 or more genes) encode
such molecules
The presence of these molecules often increases the
virulence or leads to persistence of the virus
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Surface Expression and Secretion of
Immune Modulators
HIV gp120
Normally binds to CD4 on cells to mediate attachment
Is found on the surface of HIV-infected cells
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At the cell’s surface it can bind to CD4 on other, uninfected helper T cells
This results in a death signal delivered to the T cell
Termed bystander killing
Leads to depletion of other Th cells, thus compromising the T cell repertoire
Soluble receptors for cytokines and chemokines
Large DNA viruses, including poxviruses and herpesviruses,
encode genes that are chemokine receptors
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These receptors have intrinsic signal transduction capacities, thus likely
stimulate a cellular pathway that favors the virus
Antigenic Variation
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Occurs primarily with RNA viruses
RNA polymerase has a higher mutation rate than
DNA polymerase
Can lead to subtle changes in amino acids of spike
proteins (termed antigenic drift)
These changes can reduce the capacity of antibodies to
bind viral antigens
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Subversion of Immune Response
Pathways
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Inducible Nitric Oxide Synthase (iNOS)
Inflammatory pathway during infections
Produces nitric oxide in the tissues
Part of the type I IFN pathway
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Viruses that disable the type I IFN pathway frequently disable iNOS
activity as well
Some viruses turn iNOS on to induce inflammation, which can help
in viral dissemination (e.g., Ebola Zaire)
Interference With Toll-Like Receptors
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Toll-like receptors (TLR) are surface receptors on leukocytes that
recognize distinct pathogen-associated molecular patterns (PAMP;
aka, pattern recognition receptors)
These patterns are not found in vertebrate cells, only microbes
TLRs are important signal transduction initiators that activate
immune response pathways in cells
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By interfering with TLRs and their pathways, viral proteins disable the signal
transduction events required for immune activation
Two important downstream events of TLR signaling are the activation of two
transcription factors
Nuclear factor-kappa of B cells (NF-kB, which is not B cell-specific)
Interferon response factor 3 (IRF3)
Without activation of these two factors, antiviral genes do not get turned on
Complement Inhibition
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Herpes simplex virus glycoprotein C-1
Binds to, and inactivates, the C3b complement protein
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Complement protein C9 fails to polymerize in envelope/plasma membrane (an
event downstream of C3b activation), thus no perforation occurs
Complement fails to act as an opsinin, thus phagocytosis is compromised
Monkeypox (MPXV) D14L complement inhibitor
D14L is an ortholog of vaccinia complement control protein that
inhibits complement during infection
Central African strains of MPXV are associated with human
fatalities
In 2003, an outbreak of MPXV occurred in the United States
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The strain was from West Africa
All cases were mild, with no fatalities
Genome sequencing determined the strain was missing the D14L gene
Inhibition of Cytokines and
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Chemokines
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Some viruses encode soluble cytokine receptors
These are released from the infected cell and bind to cytokines, thus
neutralizing them
Viral cytokines
Some viruses encode cytokines that modulates the immune
response
Epstein-Barr virus interleukin-10 (vIL-10)
EBV infects human B cells
It encodes an intron-free IL-10
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The absence of introns indicates that an IL-10 mRNA was reverse-transcribed
into cDNA before incorporation in the EBV genome
The sequence is more similar to human IL-10 than to any other known IL-10
sequence
The vIL-10 is secreted from infected B cells and binds to other B
cells
IL-10 and vIL-10 induce B cell proliferation
This results in new target cells for progeny virus
Blockade of T Cell Responses
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MHC Class I antigen processing and presentation
Many viruses impair the class I pathway, thus blocking CD8 CTL
responses
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Herpes simplex virus ICP47 protein binds to TAP and prevents translocation
of peptides into the lumen of the ER
Human cytomegalovirus US6 protein binds to TAP and inhibits ATP binding
HCMV US2 and US11, and mouse hepatitis virus mK3 proteins dislocate
class I proteins from the ER to the cytoplasm
Murine CMV m152 protein arrests class I-peptide vesicles at the ER/Golgi
interface
Class II inhibition blocks CD4 helper T cell responses
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EBV gp42 protein is secreted from infected B cells and binds to class II in
such a way as to impede TCR docking with the class II/peptide complexes
HIV nef protein binds to CD4 precursors in the Golgi and prevents its
maturation
Cell Death Manipulation
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Interference with apoptotic mechanisms of CTL-induced cell
death
The vertebrate Bcl-2 protein prevents apoptosis
It is expressed by lymphocytes
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It is a control protein that is required to prevent apoptosis
The cells remain alive so long as Bcl-2 is present (i.e., rescues
lymphocytes from apoptosis)
When a CTL delivers a death signal to an infected cell, Bcl-2 expression is
turned off, resulting in the cell’s death
EBV encodes BHRF1, a Bcl-2 homologue that prevents CTL-induced
death of EBV-infected B cells