病毒学双语版Chapter62

Chapter

6:

InfectionInfection:Part

2Slide

1/38<<

Part

1Chapter

6:

InfectionEvasion

of

Immune

Responsesby

VirusesSlide

1/38Inhibition

of

MHC

I-Restricted

Antigen

Presentation:

CTLs

can

only

respond

to

foreign

antigens

presentedby

MHC

I

complexes

on

the

target

cell.

Anumber

of

viruses

interfere

with

MHC

I

expression

orfunction

to

disrupt

this

process

&

evade

the

CTLresponse.

Such

mechanisms

include

downregulation

of

MHC

Iexpression

by

adenoviruses

&

interference

with

theantigen

processing

required

to

form

an

MHC

I-antigencomplex

by

herpesviruses.Chapter

6:

InfectionEvasion

of

Immune

Responsesby

VirusesSlide

1/38Inhibition

of

MHC

II

Restricted-Antigen

Presentation:

MHC-II

antigens

are

essential

in

the

adaptive

immuneresponse

in

order

to

stimulate

the

development

of

antigen-responsive

clones

of

effector

cells.

Herpesviruses

&

papillomaviruses

interfere

with

theprocessing

&

surface

expression

of

MHC

II-antigencomplexes,

inhibiting

the

CTL

response.Inhibition

of

Natural

Killer

Cell

Lysis:The

poxvirus

Molluscumcontagiosumencodes

a

homologueof

MHC

I

which

is

expressed

on

the

surface

of

infected

cellsbut

is

unable

to

bind

an

antigenic

peptide,

thus

avoidingkilling

by

NK

cells

which

would

be

triggered

by

the

absenceof

MHC

I

on

the

cell

surface.

Similar

proteins

are

made

by

other

viruses

such

as

HHV-5(CMV),

&

herpesviruses

in

general

appear

to

have

a

numberof

sophisticated

mechanisms

to

avoid

NK

cell

killing.Chapter

6:

InfectionEvasion

of

Immune

Responsesby

VirusesSlide

1/38Inhibition

of

Cytokine

Action:

Cytokines

are

secreted

polypeptides

that

co-ordinateimportant

aspects

of

the

immune

response,

includinginflammation,

cellular

activation,

proliferation,differentiation,

&

chemotaxis.

Some

viruses

are

able

to

inhibit

the

expression

of

certainchemokines

directly.

Herpesviruses

&

poxviruses

encode

"viroceptors"

-

virushomologs

of

host

cytokine

receptors

which

compete

withcellular

receptors

for

cytokine

binding

but

fail

to

give

trans-membranesignals.

High-affinity

binding

molecules

may

also

neutralize

cytokines

directly,

&

molecules

known

as

"virokines"

blockcytokine

receptors

again

without

activating

the

intracellularsignalling

cascade.Chapter

6:

InfectionEvasion

of

Immune

Responsesby

VirusesSlide

1/38Interference

with

ApoptosisVirus

Resistance

to

Interferons:

Epstein-Barr

virus

EBER

RNAs

are

similar

in

structure

&function

to

the

adenovirus

VA

RNAs.

TheEBNA-2protein

also

blocks

interferon-induced

signaltransduction

Vaccinia

virus

is

known

to

show

resistance

to

the

antiviraleffects

of

interferons.

One

of

the

early

genes

of

this

virus,

K3L,

encodes

a

proteinwhich

is

homologous

to

eIF-2 which

inhibits

the

action

ofPKR.

In

addition,

the

E3L

protein

also

binds

dsRNA

&inhibits

PKR

activation

Poliovirus

infection

activates

a

cellular

inhibitor

of

PKR

invirus-infected

cells

Reovirus

capsid

protein 3

is

believed

to

sequester

dsRNA&

therefore

prevent

activation

of

PKRChapter

6:

InfectionEvasion

of

Immune

Responsesby

VirusesSlide

1/38Evasion

ofHumoral

Immunity:

Although

directhumoral

immunity

is

less

significantthan

cell-mediated

immunity,

the

anti-viral

action

ofADCC

&

complement

make

this

a

worthwhile

target

toinhibit.

Themost

frequent

means

of

subverting

the

humoralresponse

is

by

high

frequency

genetic

variation

of

theB

cell

epitopes

on

antigens

to

which

antibodies

bind.

This

is

only

possible

for

viruses

which

are

geneticallyvariable,

e.g.

influenza

virus

&

HIV.

Herpesviruses

use

alternative

strategies

such

asencoding

viral

Fc

receptors

to

prevent

Fc-dependentimmune

activation.Chapter

6:

InfectionEvasion

of

Immune

Responsesby

VirusesSlide

1/38Evasion

of

the

Complement

Cascade:

Poxviruses,

herpesviruses

&

retrovirus

families

encodemimics

of

normal

regulators

of

complement

activationproteins,

e.g.

secreted

proteins

which

block

C3convertase

assembly

&

accelerate

its

decay.

Poxviruses

can

also

inhibit

C9

polymerization,preventing

membrane

permeabilization.Chapter

6:

InfectionVirus-Host

Interactions

For

all

viruses,pathogenic

or

non-pathogenic,

the

firstfactor

whichinfluences

the

courseof

infection

is

themechanism

&

site

ofentry

into

the

body:Slide

1/38Chapter

6:

InfectionThe

Skin:Slide

1/38

Mammalian

skin

is

a

highly

effective

barrier

againstviruses.

The

outer

layer

(epidermis)

consists

of

dead

cells

&therefore

does

not

support

virus

replication.

Very

few

viruses

infect

directly

by

this

route

unlessthere

is

prior

injury

such

as

minor

trauma

or

punctureof

the

barrier,

such

as

insect

or

animal

bites

orsubcutaneous

injections.

Some

viruses

which

do

use

this

route

are

herpes

simplex

virus

&

papillomaviruses,

although

theseviruses

probably

still

require

some

form

of

disruptionof

the

skin

such

as

small

abrasions

or

eczema.Chapter

6:

InfectionMucosal

Membranes:Slide

1/38

The

mucosalmembranesof

the

eye

&

genitourinary(GU)

tract

are

much

more

favourable

routes

ofaccess

for

viruses

to

the

tissues

of

the

body.

This

is

reflected

by

the

number

of

viruses

which

canbe

sexually

transmitted;

virus

infections

of

the

eyeare

also

quite

common.Chapter

6:

InfectionThe

Alimentary

Canal:Slide

1/38

Viruses

may

infect

the

alimentary

canal

via

the

mouth,oropharynx,

gut,

or

rectum,

although

viruses

which

infectthe

gut

via

the

oral

route

must

survive

passage

through

thestomach,

an

extremely

hostile

environment

with

a

very

lowpH

&

high

concentrations

of

digestive

enzymes.

The

gut

is

a

highly

valued

prize

for

viruses

-

the

intestinalepithelium

is

constantly

replicating

&

there

is

a

good

dealof

lymphoid

tissue

associated

with

the

gut

which

providesmany

opportunities

for

virus

replication.

Moreover,

the

constant

intake

of

food

&

fluids

providesample

opportunity

for

viruses

to

infect

these

tissues.

To

counteract

this

problem,

the

gut

has

many

specific

(e.g.

secretory

antibodies)

&

non-specific

(e.g.

stomach

acids

&

bile

salts)

defence

mechanisms.Chapter

6:

InfectionThe

Respiratory

Tract:Slide

1/38

The

respiratory

tract

is

probably

the

most

frequent

siteof

virus

infection.

As

with

the

gut,

it

is

constantly

in

contact

with

externalvirus

particles

which

are

taken

in

during

respiration.As

a

result,

the

respiratory

tract

also

has

defencesaimed

at

virus

infection

-

filtering

of

particulate

matterin

the

sinuses,

&

cells

&

antibodies

of

the

immunesystem

present

in

the

lower

regions.

Viruses

which

infect

the

respiratory

tract

usually

comedirectly

from

the

respiratory

tract

of

others,

sinceaerosol

spread

is

very

efficient:

"coughs

&

sneezesspread

diseases".Chapter

6:

InfectionThe

Natural

Environment

is

aConsiderable

Barrier

to

VirusInfections.Slide

1/38

Most

viruses

are

relatively

sensitive

to

heat,

drying,ultraviolet

light

(sunlight),

etc,

although

a

few

types

arequite

resistant

to

these

factors.

This

is

particularly

important

for

viruses

which

are

spreadvia

contaminated

water

or

foodstuffs

-

not

only

must

theybe

able

to

survive

in

the

environment

until

they

areingested

by

another

host,

but

as

most

are

spread

by

thefaecal-oral

route,

they

must

also

be

able

to

pass

throughthe

stomach

to

infect

the

gut

before

being

shed

in

thefaeces.

One

way

of

overcoming

environmental

stress

is

to

takeadvantage

of

a

secondary

vector

for

transmissionbetween

the

primary

hosts.Chapter

6:

InfectionInsect

Vectors

Offer

Protectionfrom

the

EnvironmentSlide

1/38Chapter

6:

InfectionVirus

TransmissionSlide

1/38Viruses

without

a

secondary

vector

must

rely

on

continuedhost-to-host

transmission,

&

have

evolved

variousstrategies

to

do

this:

Horizontal

transmission:

The

direct

host-to-hosttransmission

of

viruses.

This

strategy

relies

on

a

high

rate

of

infection

to

maintainthe

virus

population

Vertical

transmission:

The

transmission

of

the

virus

fromone

generation

of

hosts

to

the

next.

This

may

occur

by

infection

of

the

foetus

before,

during,

orshortly

after

birth

(e.g.

during

breastfeeding).

More

rarely,

it

may

involve

direct

transfer

of

the

virus

viathe

germ

line

itself,

e.g.

retroviruses.

In

contrast

to

horizontal

transmission,

this

strategy

relieson

long-term

persistence

of

the

virus

in

the

host

rather

thanrapid

propagation

&

dissemination

of

the

virus.Chapter

6:

InfectionPrimary

ReplicationSlide

1/38

Having

gained

entry

to

a

potential

host,

the

virus

mustinitiate

an

infection

by

entering

a

susceptible

cell(primary

replication).

This

initial

interaction

frequently

determines

whetherthe

infection

will

remain

localized

at

the

site

of

entry

orspread

to

become

a

systemic

infection.In

some

cases,

virus

spread

is

controlled

byinfectionof

polarized

epithelial

cells

&

the

preferential

release

ofvirus

from

either

the

apical

(e.g.

influenza

virus

-

alocalized

infection

in

the

upper

respiratory

tract)

orbasolateral

(e.g.

rhabdoviruses

-

a

systemic

infection)surface

of

the

cells.Chapter

6:

InfectionInfection

of

Polarized

EpitheliumSlide

1/38Chapter

6:

InfectionSystemic

SpreadSlide

1/38

Following

primary

replication

at

the

site

of

infection,the

next

stage

may

be

spread

throughout

the

host.

In

addition

to

direct

cell-cell

contact,

there

are

two

mainmechanisms

for

spread

throughout

the

host:

Via

the

bloodstream:

Viruses

may

get

into

thebloodstream

by

direct

inoculation,

for

example,

byarthropod

vectors,

blood

transfusion,

or

intravenousdrug

abuse

(sharing

of

non-sterilized

needles).

Via

the

nervous

system:

Spread

of

virus

to

thenervous

system

is

usually

preceded

by

primaryviraemia.Chapter

6:

InfectionClearance

vs.

PersistanceSlide

1/38Virus

clearance

is

mediated

by

the

immune

system.

However,

viruses

are

moving

targets

which

rapidly

respondto

pressure

from

the

immune

system

by

altering

theirantigenic

composition

(whenever

possible).

The

classic

example

of

this

phenomenon

is

influenza

virus,which

displays

two

genetic

mechanisms

that

allow

the

virusto

alter

its

antigenic

constitution:

Antigenic

drift:

This

involves

the

gradual

accumulation

ofminor

mutations

(e.g.

nucleotide

substitutions)

in

the

virusgenome

which

result

in

subtly

altered

coding

potential

&therefore

altered

antigenicity,

leading

to

decreasedrecognition

by

the

Antigenic

shift:

In

this

process

a

sudden

&

dramaticchange

in

the

antigenicity

of

a

virus

occurs

owing

toreassortment

of

the

segmented

virus

genome

with

anothergenome

of

a

different

antigenic

type.Chapter

6:

InfectionAntigenicVariation

inInfluenzaVirusSlide

1/38Chapter

6:

InfectionInfluenzaPandemicsSlide

1/38Chapter

6:

InfectionThe

Course

of

Virus

InfectionsSlide

1/38Patterns

of

virus

infection

can

be

divided

into

anumberofdifferent

types:

Abortive

infection:

occurs

when

a

virus

infects

a

cell

(orhost),

but

cannot

complete

the

full

replication

cycle.Therefore,

this

is

a

non-productive

infection.

Acute

infection:

many

common

virus

infections

(e.g."colds")

-

relatively

brief

infections,

where

the

virus

isusually

eliminated

completely

by

the

immune

system.

Chronic

infection:

These

are

the

converse

of

acuteinfections,

i.e.

prolonged

&

stubborn.

The

best

studiedexample

is

lymphocytic

choriomeningitis

virus

(LCMV,

anarenavirus)

infection

in

mice.

Latent

virus

infections

typically

persist

for

the

entire

life

ofthe

host,

e.g.

herpes

simplex

virus

(HSV).Chapter

6:

InfectionChronic

LCMV

Infection:Slide

1/38Chapter

6:

InfectionPrevention

&

Therapy

of

VirusInfectionsSlide

1/38

There

are

two

aspects

of

the

response

to

the

threat

of

virusdiseases:

prevention

of

infection

&

treatment

of

disease.

Theformer

strategy

relies

on

two

approaches:

public

&personal

hygiene,

which

perhaps

plays

the

major

role

inpreventing

virus

infection

(e.g.

provision

of

clean

drinkingwater

&

disposal

of

sewage;

good

medical

practice

such

asthe

sterilization

of

surgical

instruments)

&

vaccination,which

makes

use

of

the

immune

system

to

combat

virusinfections.

Mostof

the

damage

to

cells

during

virus

infections

occursvery

early,

often

before

the

clinical

symptoms

of

diseaseappear.

This

makes

the

treatment

of

virus

infection

very

difficult,

&therefore,

in

addition

to

being

cheaper,

prevention

of

virusinfection

is

undoubtedly

better

than

cure.Chapter

6:

InfectionVirus

Vaccine

DesignSlide

1/38

To

design

effective

vaccines,

it

is

important

to

understand

boththe

immune

response

to

virus

infection

&

the

stages

of

virusreplication

thatareappropriate

targets

for

immune

intervention.

To

be

effective,

vaccines

must

stimulate

as

many

of

the

body"sdefence

mechanisms

as

possible.

Inpractice,

this

usually

means

trying

to

mimic

the

disease,without

of

course

causing

pathogenesis

-

for

example,

the

use

ofnasally

administered

influenza

vaccines

&

orally

administeredpoliovirus

vaccines.To

be

effective,

it

isnotnecessary

to

get

100%

uptake

of

vaccine.

"Herd

immunity"

results

from

the

break

in

transmission

of

a

viruswhichoccurswhen

a

sufficiently

high

proportion

of

a

populationhas

been

vaccinated.

This

strategy

is

most

effective

where

there

is

no

alternative

hostfor

the

virus,

e.g.

measles,

&

in

practice

is

the

situation

thatusually

occurs

since

it

is

impossible

to

achieve

100%

coveragewith

any

vaccine.Chapter

6:

InfectionDNA

VaccinesSlide

1/38These

are

the

newest

type

of

vaccine

&

consist

of

onlya

DNA

molecule

encoding

the

antigen(s)

of

interest

&possibly,

costimulatory

molecules

such

as

cytokines.The

concept

behind

these

vaccines

is

that

the

DNAcomponent

will

be

expressed

in

vivo,

creating

smallamounts

of

antigenic

protein

which

serve

to

prime

theimmune

response

so

that

a

protective

response

canberapidly

generated

when

the

real

antigen

is

encountered.In

theory,

these

vaccines

could

be

manufacturedquickly

&

should

efficiently

induce

both

humoral

&

cell-mediated

immunity.Chapter

6:

InfectionSubunit

VaccinesSlide

1/38

These

consist

of

only

some

components

of

the

virus,

sufficient

toinduce

a

protective

immune

response

but

not

enough

to

allowany

danger

of

infection.

Ingeneralterms,

they

are

completely

safe,

exceptfor

very

rarecases

in

which

adverse

immune

reactions

may

occur.

Unfortunately,

at

present,

they

are

also

the

least

effective

&

mostexpensive

type

of

vaccines.

The

major

technical

problems

associated

with

subunit

vaccines

are

their

relatively

poor

antigenicity

&

the

need

for

new

deliverysystems,

such

as

improved

carriers

&

adjuvants.There

are

several

categories

of

such

vaccines:

Synthetic

vaccines,

such

as

short,

chemically

synthesizedpeptides.Recombinant

vaccines,

produced

by

genetic

engineering.

Virus

vectors,

i.e.

recombinant

virus

genomes

geneticallymanipulated

to

express

protective

antigens

from

(unrelated)pathogenic

viruses.Chapter

6:

InfectionInactivated

VaccinesSlide

1/38

Produced

by

exposing

the

virus

to

a

denaturing

agent

underprecisely

controlled

conditions.

The

objective

is

to

cause

loss

ofvirus

infectivity

without

loss

ofantigenicity.

Inactivated

vaccines

have

certainadvantages,such

as

generallybeing

effective

immunogens

(if

properly

inactivated),

beingrelatively

stable,

&

carrying

little

or

no

risk

of

vaccine-associatedvirus

infection

(if

properly

inactivated).

It

is

not

possible

to

produced

inactivated

vaccines

for

all

viruses,since

denaturation

of

virus

proteins

may

lead

to

loss

ofantigenicity,

e.g.

measles

virus.

Although

relatively

effective,

"killed"

vaccines

are

sometimes

notas

effective

at

preventing

infection

as

"live"

virus

vaccines,

oftenbecause

they

fail

to

stimulate

protective

mucosal

&

cell-mediatedimmunity

to

the

same

extent.

These

vaccines

may

contain

virusnucleicacids,

which

maythemselves

be

a

source

of

infection,

either

of

their

own

accord(e.g.

(+)sense

RNA

virus

genomes)

or

after

recombination

withother

viruses.Chapter

6:

InfectionLive

(Attenuated)

Virus

VaccinesSlide

1/38

Attenuated

viruses

with

reduced

pathogenicity

stimulate

animmune

responsewithoutcausing

disease.

The

vaccine

strain

may

be

a

naturally

occurring

virus

(e.g.

use

ofcowpox

virus

by

Edward

Jenner

to

vaccinate

against

smallpox)

orartificially

attenuatedin

vitro

(e.g.

oral

poliomyelitis

vaccineproduced

by

Albert

Sabin).

The

advantage

of

attenuated

vaccines

is

that

they

aregoodimmunogens

&

inducelong-lived,

appropriate

immunity.These

vaccinesmay

be

biochemically

&

genetically

unstable

&may

either

lose

infectivity

or

revert

to

virulence

unexpectedly.

Despite

intensive

study,

it

is

not

possible

to

produce

anattenuated

vaccine

to

order,

&

there

is

no

general

mechanism

bywhich

all

viruses

can

be

reliably

&

safely

attenuated.

Inappropriate

use

of

live

virus

vaccines,

for

example,

inimmunocompromised

hosts

or

during

pregnancy,

may

lead

tovaccine-associated

disease,

whereas

the

samevaccinegiven

to

ahealthy

individual

may

be

perfectly

safe.Chapter

6:

InfectionVirus

Vectors

&

Gene

TherapySlide

1/38

Viruses

are

being

developed

as

gene

delivery

systems

forthe

treatment

of

inherited

&

also

acquired

diseases.

The

first

human

trial

to

treat

children

withimmunodeficiency

resulting

from

a

lack

of

the

enzymeadenosine

deaminase(ADA)began

in

1990

&

showedencouraging

results.

Like

most

of

the

initial

attempts,

thistrial

used

recombinant

retrovirus

genomes

as

vectors.

A

variety

of

different

viruses

are

now

being

tested

aspotential

vectors

&

a

large

number

of

different

trials

areunderway.

Non-virus

methods

of

gene

delivery

includingliposome/DNA

complexes,

peptide/DNA

complexes

&

directinjection

of

recombinant

DNA

are

also

under

activeinvestigation.Chapter

6:

InfectionChemotherapy

of

Virus

InfectionsSlide

1/38

Thealternative

to

vaccination

is

to

attempt

to

treat

virusinfections

using

drugs

which

block

virus

replication.

Historically,

discovery

of

antiviral

drugs

has

been

largelyfortuitous.

Spurred

on

by

successes

in

the

treatment

of

bacterialinfections

with

antibiotics,

drug

companies

launched

hugeblind-screeningprogrammes

to

identify

chemicalcompounds

with

antiviral

activity,

with

relatively

littlesuccess.

The

key

to

the

success

of

any

antiviral

drug

lies

in

itsspecificity.

Almost

any

stage

of

virus

replication

can

be

a

target

for

adrug,

but

the

drug

must

be

more

toxic

to

the

virus

than

thehost.Chapter

6:

InfectionAny

of

the

Stages

of

VirusReplication

can

be

A

Target

forAntiviral

Intervention.Slide

1/38The

attachment

phase

of

replication

can

be

inhibited

intwo

ways:

by

agents

which

mimic

the

virus-attachment

protein(VAP)

&

bind

to

the

cellular

receptorbyagents

which

mimic

the

receptor

&

bind

to

the

VAP

It

is

difficult

to

target

specifically

the

penetration/uncoating

stages

of

virus

replication

as

relatively

littleis

known

about

them.

Uncoating

in

particular

is

largely

mediated

by

cellularenzymes&

is

therefore

a

poor

target

for

intervention,although

like

penetration,

it

is

often

influenced

by

oneor

more

virus

proteins.Chapter

6:

InfectionAmantadine

&

RimantadineSlide

1/38

Amantadine

&

Rimantadine

are

active

against

influenza

Aviruses.

The

action

of

these

closely

related

agents

is

to

blockcellular

membrane

ion

channels.

The

target

for

both

drugs

is

the

influenza

matrix

protein(M2),

but

resistance

to

the

drug

may

also

map

to

thehemagglutinin

gene.

This

biphasic

action

results

from

the

inability

of

drug-treated

cells

to

lower

the

pH

of

the

endosomal

compartment(a

function

normally

controlled

by

the

M2

gene

product),which

is

essential

to

induce

conformational

changes

in

theHA

protein

to

permit

membrane

fusion.Chapter

6:

InfectionNucleoside

AnaloguesSlide

1/38

Many

viruses

have

evolved

their

own

specific

enzymes

toreplicate

virus

nucleic

acids

preferentially

at

the

expense

ofcellular

molecules.

There

is

often

sufficient

specificity

in

virus

polymerases

toprovide

a

target

for

an

antiviral

agent,

&

this

method

hasproduced

the

majority

of

the

specific

antiviral

drugscurrently

in

use.

The

majority

of

these

drugs

function

as

polymerasesubstrates

(i.e.

nucleoside/nucleotide)

analogues,

&

theirtoxicity

varies

considerably

from

some

which

are

welltolerated

(e.g.

acyclovir)

to

others

which

are

quite

toxic

(e.g.AZT).

There

is

a

problem

with

the

pharmacokinetics

of

thesenucleoside

analogues

-

their

typical

serum

half-life

is

1-4

h.Chapter

6:

InfectionNucleoside

AnaloguesSlide

1/38Nucleoside

analogues

are,

pro-drugs,

since

they

need

to

bephosphorylated

before

becoming

effective.

This

is

the

keyto

their

selectivity:

Acyclovir

is

phosphorylated

by

HSV

thymidine

kinase

200times

more

efficiently

than

by

cellular

enzymes

Ganciclovir

is

10times

more

effective

against

CMV

thanacyclovir,

but

must

be

phosphorylated

by

a

kinase

encodedby

CMV

gene

UL97

before

it

becomes

pharmaceuticallyactive

A

series

of

other

nucleoside

analogues

derived

from

thesedrugs

&

active

against

herpesviruses

have

been

developed,e.g.

valciclovir

&

famciclovir. These

compounds

haveimproved

pharmacokinetic

properties

such

as

better

oralbioavailability

&

longer

half

lives.Chapter

6:

InfectionNon-Nucleoside

AnaloguesSlide

1/38

Foscarnet

is

an

analogue

of

pyrophosphate

which

interferes

withthe

binding

of

incomingnucleotidetriphosphates

by

virus

DNAp