IMMUNITY TO VIRUSES

MBChB/BDS III
tshabalala@zappuz.co.zw mqondisi@buffalo.edu mtshabaz@gmail.com

Outline
Viral tropism and general biology Innate immunity to viral infections Specific Immunity (humoral and cell mediated) Evasion of host immune responses Discussion points/take home message

Background
Viruses are intracellular microbes, use host

biosynthetic machinery for survival=obligatory effects (lytic) e.g. T cell apoptosis in HIV infection lytic)= virus resides in cells but produce

Viral replication within cells lead to cytopathic

Some viruses dont cause cytopathic effects (non

proteins to which specific immunity is raised=

latent infections
Host IR to cytopathic and non cytopathic viral

infections are different

Viral tropism
Utilize natural/normal cellular receptors to gain entry

and infect host cells

Infect a wide variety of cells using normal cell surface

receptors

HIV CD4, CCR EBV CR2 (complement receptor on B cells, CD21 Rhinovirus ICAM-1(on most cells), CD54

Viral antigens are dominantly proteins or glycoproteins Internal antigens are usually not relevant to protective

immunity

Innate Immunity

Phagocytosis Neutrophils, Macrophages Viral infection directly stimulates production of IFN by infected cells IFN () released from virus infected cells induce antiviral state in neighboring uninfected cells coupled with high MHC 1 expression

IFN cont.
Cells produce enzymes e.g. 2-5

oligoadenylate synthatase that inhibit viral rep. Increase lytic potential of NK cells Up regulation of MHC I (efficient CTL), but inhibit MHC II ??? Clinical use of cytokine e.g. antiviral agent in viral hepatitis, HPV

Innate Immunity

NK cells lyse a wide variety of virally infected cells (peforins, granzymes, proteoglycans)

NK Cell

Specific humoral IRs

Humoral IRs target viruses before entry into

host cells, and are less effective in intracellularly replicating viruses

NB: IRs to virions are mostly humoral whilst CTLs target virally infected cells

Specific humoral IRs

Specific Ab in early course of infection

neutralising Abs prevent viral attachment by

targeting specific viral antigens e.g. haemaglutinin of influenza virus more neutralising than Ab to other sites

Prevent viral attachment and entry

Complement assists neutralization by coating

virus or lysing those with lipid membranes

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Neutralisation

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Complement Activation

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Specific humoral IRs

Opsonising Ab enhance phagocytic clearance

of viral particles

NB opsonisation may also enhance invasion of Fc-receptor bearing cells by virus e.g HIV infection of mononuclear cells Ab may also result in modulation/stripping of viral antigens from cell surface allowing infected cells to avoid destruction by cytotoxic cells.

NB Ab bind to virus then their Fc receptors are recognized by phagocytes

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Opsonisation

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Specific humoral IRs

Antibody dependent cell mediated

cytotoxicity (ADCC) NKs are major effector cells infected cell

NK cell mediated lysis of Ab coated virus

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ADCC

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Points to note in humoral

Ab important before viral entry

into cell: intracellular viruses are untouchable Purified Ab based vaccines have shown less protection In vitro protection (experiments) not correlated to in vivo protection IS AB BASED IRs ENOUGH TO PROTECT FROM VIRAL INFECTIONS?
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Specific CTL IRs

CTLs physiological function of

immunesurveillance of viral infection Principal mechanism against established viral infections especially non-cytopathic viruses CD8 T cells recognize viral antigen in association with MHC class I. CTLs require CD4 Th cytokines IL-2, IFN-g or costimulators expressed on APC CTLs lead to specific cell lysis, enzymatic lysis of viral particles, cytokine secretion (interferon activity)

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CTL

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Specific CTL IRs

Despite the strong CTL IRs, progression of

viral disease suggesting the importance of both Innate and specific (humoral and CTL) in controlling viral infections

e.g. influenza specific CTLs target matrix protein and nucleoprotein (internal proteins) whilst Ab target envelope glycoproteins (hemagglutinin and neuraminidase)

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Specific CTL IRs

Involvement of macrophages Immune responses may produce disease esp non

cytopathic viruses Killing of cells that are infected but not injured by virus Persistent viral infection e.g. HBV resulting in formation of circulating immune complexes of viral particles and specific Ag, - systemic vasculitis Autoimmunity molecular mimicry (viral a.a seq similar to self Ag)
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Escaping IRs by viruses

Antigenic variation (serologically

distinct strains of viruses) e.g. influenza epidemics of 1918, 1957, 1968; HIV mutation!

Antigenic drift (minor genetic change), antigenic shift (major genetic change)
Inhibition of MHC I presentation of Ag

Suppression of transcription of MHC I genes (Adenovirus type 12) Inhibition of antigen processing (HSV, CMV)
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Escaping IRs by viruses

Inhibition of innate or specific immunity

Production of molecules homologous to MHC I (CMV) and receptors of several cytokines (Pox virus) =compete with normal receptors needed for IR

Lysis or inactivation of immunocompetent

cells HIV CD4 T cell apoptosis

IR inhibition by mols mimicking normal

immunomodulators=competition by mol mimicry e.g. EBV produces macrophage suppressive IL10 mimic

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Discussion points
Immune response to some antigens may be much more

effective than to others

Response could be beneficial or detrimental e.g.

autoimmunity, hypersensitivity e.g. mice models show CTLs for lymphocytic choriomeningitis virus (LCMV) leading to spinal cord meninges

Transformation of host cells e.g. oncogenic viruses

Remember to READ READ READ

(leukemias-HTLV-1)

READ!!!!

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FDA Approves H1N1 Vaccine, Ebola kills hundreds, Mosquitoes and DENGUE virus

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