Unit 2 - Lecture 11 Anti-viral Immunotherapy and Vaccines Flashcards
What are the host constraints of Viral life Cycle?
- Replication and transfer to a new host are essential for viral existence
- Processes associated with the viral replication cycle make the virus vulnerable to immune control mechanisms
‘warning’ the host of the presence of an invader
production of antigenic viral proteins
- Viruses have evolved strategies to evade such immune control mechanisms
What are Viral Evasion Strategies?
- Many of the viruses that evade the immune system establish persistent and chronic infections.
Mutation, thereby escaping neutralizing antibodies and the cytotoxic CD8 T cell response
Latency and molecular mimicry
Certain viruses overexpress soluble viral antigens that bind all of host’s circulating antibodies
Viruses inactivate cytokine signals
Viruses inactivate immune cells
Viruses block cellular pathways
Apoptosis
Complement
IFN pathways
What is Antigenic variability?
- Low fidelity of RNA polymerases means RNA viruses comprise a collection of quasispecies with random mutations
- Generation/selection of variants with different antigenic properties that can evade recognition by neutralizing antibodies
- New antigens that do not bind to major histocompatibility complex (MHC) molecules
What is involved in Antigenic Variability?
What is Drift?
What is Shift?
What is Viral Latency?
- Some viruses adopt a latent life cycle
- Dormant; not fully replicating, few viral proteins being produced
Episomal latency: viral genes “floating” in cytoplasm or nucleus
Proviral latency: integration into host genome
- Lifelong, persistent infection
Residence in long-lived cells (T cells, B cells)
Little/no recognition by CD8 cytotoxic T cells or NK cells
Virus can reactivate at any time and begin producing viral progeny
E.g., Herpes simplex viruses, Epstein-Barr virus, HIV, CMV, Varicella zoster
What is involved with Viral Families and Immune Evasion?
DNA vs. RNA virsuses
Viruses that belong to different families are subject to different constraints:
RNA viruses
- use mutation to escape immune control
- little room in the genome to allow immune defenses to be encoded by individual genes
- Multi-functional proteins
DNA viruses
- Larger genome size allows for a greater number of genes to be devoted to host control
- Such genes probably account for >50% of the total genome (herpesviruses, poxviruses).
What are viral immunoregulatory proteins?
- Two classes of viral immunoregulatory proteins:
- Encoded by genes with sequence homology to cellular genes
- Encoded by genes without homology
- Viral homologs of host genes involved in the immune system are mainly found in large DNA viruses
‘stolen’ genes from the host subsequently modified for the benefit of the virus
- Proteins lacking homology might possess specific motifs required for interaction with the host cellular machineries.
What is Viral Evasion of Type I interferon?
- Type I interferons (IFNs) represent the body’s first anti-viral defense mechanism
- Inhibition of cell-signaling pathways involved in inducing the “anti-viral state” in infected cells
- Inhibition of interferon-stimulated genes
- PKR, Oas1b, Rnase L (Chapter 7 in text)
- Soluble receptors that block the ability of IFN to bind to host cell surface receptors (IFN-R)
- Block production of cytokines that activate the type I interferon pathway.
What is Viral Evasion of Complement?
Viruses encode homologs of complement regulatory proteins that are secreted and block complement activation and neutralization of virus particles
- inhibitors of the membrane-attack complex
- inhibiting production of the macrophage chemoattractant factors C3a and C5a (coxpox virus inflammation modulatory protein)
- incorporating host cellular protective factors into the viral envelope.
What are Viral Modulation of Cytokine & Chemokines?
- Large DNA viruses encode mimics of host cytokines (virokines) and cytokine receptors (viroceptors)
- Soluble viroceptors neutralize cytokine activity
- Virokines may redirect immune responses to the benefit of the virus
Inhibit inflammation
- Virokines may induce signaling pathways in infected cells to promote virus replication
- Virokines may also increase proliferation of cells that are targets for viral infection
- Virus-encoded chemokines are either:
- *Antagonists**: blocking immune cell recruitment to sites of infection
- *Agonists:** enhance recruitment of cells that support viral replication
What is the viral regulation of Apoptosis and cell cycle?
- Virus infection/replication is often associated with apoptosis (programmed cell death)
- Most viruses encode proteins that can inhibit apoptosis:
- *–Bcl-2** homologs; inhibit activation of apoptosis
- -p53 inhibitors; inhibit pro-apoptotic protein expression
- –Caspase inhibitors; block proteolytical degradation of host intracellular proteins
- –Block effects of molecules known to initial apoptosis (TNF and Fas)
- Viruses can be exported in apoptotic bodies to avoid activation of innate immune system
What are HIV-mediated Destruction of CD4 T cells?
- HIV infects CD4 T cells, replicates, and releases new HIV particles.
- Viral progeny infect other CD4 T cells, killing the cells and reducing the body’s CD4 T cell count (<200 per microliter of blood)
- Viral-specific CD4 T cells are more susceptible to infection.
- Immune system weakened
- Reduction in HIV-specific antibody production
What is the Evasion of MHC class I antigen Presentation Pathway?
MHC class I pathway is critical for the activation of anti-viral cytotoxic CD8 T cells.
Immunomodulatory proteins
- Proteasomal inhibitors allow viral proteins to escape processing.
- Block peptide-loading
- Block transport of MHC class I molecules from the ER to the cell surface
- Induce endocytosis and degradation of cell surface MHC class I
What is Viral Evasion of NK cell Activation?
How does it recognize the cells?
What is the evasion mechanisms?
NK cells are the prime effector innate cell type targeting virally infected cells
- Down Regulation of MHC class I is a common respons in virally infected cells.
- BAclance of + and - signals
Evasion mechanisms:
- Increase expression of inhibitory ligands
- Down regulate expression of activating ligands
- Express viral mimcs of inhibitory ligands and/or MHC class I.
- Disrupt release of effector molecules
Fundamental concepts
- Despite a host’s nonspecific and specific immune defenses, viruses have evolved ways to evade immune responses.
- Most significant form of immune evasion involves mutation to avoid antibodies and cytotoxic T cells
- RNA viruses with smaller genomes
- Viruses can “hide” by adopting a latent life cycle
- HIV, EBV, CMV
- Viruses may also encode multiple immunomodulatory proteins
- DNA viruses with larger sized genomes
- Viral products may inactivate the anti-viral interferon pathways and PRR signaling pathways
- Viral products may inactivate the complement pathway to prevent lysis
- Viruses may inactivate cytokines and their receptors, thus reducing the efficacy of the immune response
- Manipulation of the MHC class I pathway allows viruses to escape killing by CD8 cytotoxic T cells
- Viruses are capable of evading NK cell function
- Some viruses manipulate apoptotic pathways in host cells to prevent cell death
