Immunity to Viruses - Mbchb Iii_2011(1)

8/2/2019 Immunity to Viruses - Mbchb Iii_2011(1)

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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


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Background Viruses are intracellular microbes, use host

biosynthetic machinery for survival=obligatory

Viral replication within cells lead to cytopathic

effects (lytic) e.g. T cell apoptosis in HIV infection

Some viruses dont cause cytopathic effects (nonlytic)= virus resides in cells but produceproteins to which specific immunity is raised=latent infections

Host IR to cytopathic and non cytopathic viralinfections are different


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Viral tropism Utilize natural/normal cellular receptors to gain entry

and infect host cells

Infect a wide variety of cells using normal cell surfacereceptors

HIVCD4, CCR

EBVCR2 (complement receptor on B cells, CD21

RhinovirusICAM-1(on most cells), CD54

Viral antigens are dominantly proteins or glycoproteins

Internal antigens are usually not relevant to protectiveimmunity


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Innate Immunity

PhagocytosisNeutrophils,

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


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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


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Innate Immunity

NK cells lyse a wide variety of virally

infected cells (peforins, granzymes,

proteoglycans)


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NK Cell


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Specific humoral IRs

Humoral IRs target viruses before entry into

host cells, and are less effective inintracellularly replicating viruses

NB: IRs to virions are mostly humoral whilst

CTLs target virally infected cells


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Specific Ab in early course of infection neutralising Absprevent 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 coatingvirus or lysing those with lipid membranes


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Neutralisation


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Complement Activation


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Opsonising Abenhance phagocytic clearanceof viral particles

NB opsonisation may also enhance invasionof Fc-receptor bearing cells by virus e.g HIV

infection of mononuclear cells

Ab may also result in modulation/stripping ofviral antigens from cell surface allowinginfected 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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Antibody dependent cell mediated

cytotoxicity (ADCC)NKs are major effector

cells

NK cell mediated lysis of Ab coated virusinfected cell



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ADCC


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Points to note in humoral

Ab important before viral entry

into cell: intracellular viruses areuntouchable

Purified Ab based vaccines have

shown less protection

In vitroprotection (experiments)

not correlated to in vivo

protection

IS AB BASED IRs ENOUGH TOPROTECT 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 cytokinesIL-2, IFN-g or

costimulators expressed on APC

CTLs lead to specific cell lysis, enzymatic lysisof 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) incontrolling 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 notinjured by virus

Persistent viral infection e.g. HBV resulting information of circulating immune complexes ofviral particles and specific Ag, - systemicvasculitis

Autoimmunitymolecular mimicry (viral a.aseq 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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Discussion points

Immune response to some antigens may be much moreeffective than to others

Response could be beneficial or detrimental e.g.autoimmunity, hypersensitivity e.g. mice models showCTLs for lymphocytic choriomeningitis virus (LCMV)leading to spinal cord meninges

Transformation of host cells e.g. oncogenic viruses(leukemias-HTLV-1)

Remember to READ READ READREAD!!!!


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Immunity to Viruses - Mbchb Iii_2011(1)

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