Viral Evasion StrategiesSupplement to Chapter 8

Finlay and McFadden. 2006. Cell. 124:767-782

Viral Evasion

• 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

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• 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 • These receptors have intrinsic signal transduction capacities, thus

likely stimulate a cellular pathway that favors the virus

Antigenic Variation

• 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

Subversion of Immune Response Pathways

• Inducible Nitric Oxide Synthase (iNOS)

• Inflammatory pathway during infections

• Produces nitric oxide in the tissues

• Part of the type I IFN pathway• 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• 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• 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• Herpes simplex virus glycoprotein C-1

• Binds to, and inactivates, the C3b complement protein• 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• 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 Chemokines• Cytokine decoys

• 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• 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• MHC Class I antigen processing and presentation

• Many viruses impair the class I pathway, thus blocking CD8 CTL responses• 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• 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

• Interference with apoptotic mechanisms of CTL-induced cell death

• The vertebrate Bcl-2 protein prevents apoptosis

• It is expressed by lymphocytes• 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