You are on page 1of 105

MICROBIOLOGY LECTURE SERIES

LUZ GREGORIA LAZO-VELASCO, MD

GENERAL PROPERTIES OF
VIRUSES
Smallest infectious agents (20nm-300nm
in diameter)
Contain only one kind of nucleic acid
(RNA or DNA) as their genome
Nucleic acid is encased in a protein shell
which may be surrounded by a lipdcontaining membrane
VIRION entire infectious unit
Inert in the extracellular environment;
replicate only in living cells

GENERAL PROPERTIES OF
VIRUSES
Viral nucleic acid contains information
necessary for programming the
infected host cell to synthesize virusspecific macromolecules required for
the production of viral progeny
During the replicative cycle, numerous
copies of viral nucleic acid and coat
proteins are produced

GENERAL PROPERTIES OF
VIRUSES
Coat proteins assemble together to
form the capsid (encases and
stabilizes the viral nucleic acid against
the extracellular environment;
facilitates the attachment and
penetration by the virus upon contact
with new susceptible cells)

GENERAL PROPERTIES OF
VIRUSES
Rich in diversity viruses vary greatly
in structure, genome organization
and expression, strategies of
replication and transmission
Host range maybe broad or extremely
limited
Known to infect unicellular organisms
such as mycoplasmas, bacteria and
algae and all higher plants and
animals

TERMS AND DEFINITIONS IN


VIROLOGY
CAPSID protein shell, or coat, that
encloses the nucleic acid genome
CAPSOMERES morphologic units
seen in the electron microscope on
the surface of icosahedral virus
particles
DEFECTIVE VIRUS virus particle
that is functionally deficient in some
aspect of replication

TERMS AND DEFINITIONS IN


VIROLOGY
ENVELOPE lipid-containing
membrane that surrounds some virus
particles
NUCLEOCAPSID protein-nucleic
acid complex representing the
packaged form of the viral genome
STRUCTURAL UNITS basic protein
building blocks of the coat; usually a
collection of >1 non-identical protein
subunit

TERMS AND DEFINITIONS IN


VIROLOGY
SUBUNIT a single folded viral
polypeptide chain
VIRION complete virus particle;
serves to transfer the viral nucleic acid
from one cell to another

EVOLUTIONARY ORIGIN OF
VIRUSES
Origin of viruses not known
2 theories:
1. Viruses may be derived from
DNA or RNA nucleic acid components of
host cells that became able to replicate
autonomously and evolve
independently
2. Viruses may be degenerate
forms of intracellular parasites

CLASSIFICATION OF VIRUSES
BASIS OF CLASSIFICATION
1. Virion morphology, size, shape, type of
symmetry, presence or absence of peplomers,
and presence or absence of membranes
2. Virus genome properties, including type of
nucleic acid (DNA or RNA), size of genome (kb
or kbp), strandedness (single or double),
whether linear or circular, sense (positive,
negative, ambisense), segments (number,
size), nucleotide sequence, G + C content, and
presence of special features [repetitive
elements, isomerization, 5'-terminal cap, 5'terminal covalently linked protein, 3'-terminal
poly(A) tract]

CLASSIFICATION OF VIRUSES
BASIS OF CLASSIFICATION
3. Genome organization and replication,
including gene order, number and position of
of open reading frames, strategy of replication
(patterns of transcription, translation), and
cellular sites (accumulation of proteins, virion
assembly, virion release)
4. Virus protein properties, number, size, and
functional activities of structural and
nonstructural proteins, AA sequence,
modifications (glycosylation, phosphorylation,
myristylation), and special functional activities
(transcriptase, reverse transcriptase,
neuraminidase, fusion activities)

CLASSIFICATION OF VIRUSES
BASIS OF CLASSIFICATION
5. Antigenic properties

6. Physicochemical properties of the virion,


including molecular mass, buoyant
density, pH stability, thermal stability, and
susceptibility to physical and chemical
agents, especially ether and detergents
7. Biologic properties, including natural host
range, mode of transmission, vector
relationships, pathogenicity, tissue
tropisms, and pathology

UNIVERSAL SYSTEM OF VIRUS


TAXONOMY
Viruses are separated into FAMILIES on the
basis of virion morphology, genome
structure and strategies of replication
Virus family names have the suffix viridae
Genera subdivisions based on biological,
genomic, physicochemical or serologic
differences; genus names carry the suffix
virus
Subfamilies have been defined in several
families
Order

DNA VIRUSES
A. Parvoviruses
Human parvovirus B19 aplastic
crisis, fifth disease, fetal death
B. Anelloviruses
C. Polyomaviruses
JC virus progressive multifocal
leukoencephalopathy
BK virus nephropathy in transplant
recipients
Merkel cell virus - Merkel cell skin CA

DNA VIRUSES
D. Papillomaviruses
wart viruses
E. Adenoviruses- acute respiratory
diseases, conjuctivitis ,
gastroenteritis
F. Hepadnaviruses acute and
chronic hepatitis

DNA VIRUSES
G. Herpesviruses
Herpes simplex type 1 & 2 (oral &
genital lesions)
Varicella-zoster virus (chickenpox &
shingles)
Cytomegalovirus
Epstein-Barr virus (infectious
mononucleosis, assoc. with human neoplasms)
Human herpesvirus 6 & 7 (T
lymphocytic)
Human herpesvirus 8 (Kaposi sarcoma)

DNA VIRUSES
H. Poxviruses
smallpox
vaccinia
molluscum contangiosum
cowpox
monkeypox

RNA VIRUSES
A. Picornaviruses
Enteroviruses (polioviruses,
coxsackieviruses, and echoviruses,
rhinoviruses (common colds) and
hepatoviruses (Hepatitis A)
B. Astroviruses- gastroenteritis
C. Caliciviruses
Noroviruses (Norwalk virus)
epidemic acute gastroenteritis

RNA VIRUSES
D. Hepeviruses
Human Hepatitis E virus
E. Picobirnaviruses
F. Reoviruses
Rotaviruses (wheel-shaped appearance;
gastroenteritis)
G. Arboviruses and Rodent-Borne Viruses
Dengue Virus
Yellow fever virus
West Nile fever virus
Encephalitis virus

RNA VIRUSES
H. Togaviruses
Rubella virus
I. Flaviviruses
Hepatitis C virus
J. Arenaviruses
K. Coronaviruses
colds
SARS (severe acute respiratory
syndrome)

RNA VIRUSES
L. Retroviruses
AIDS
M. Orthomyxoviruses
Influenza viruses
N. Bunyaviruses
O. Bornaviruses
P. Rhabdoviruses
Rabies virus
Q. Paramyxoviruses
Mumps, measles, parainfluenza,
metapneumo & respiratory syncytial viruses

RNA VIRUSES
R. Filoviruses
Marburg virus
Ebola virus

severe hemorrhagic
fever in Africa

PRINCIPLES OF VIRUS STRUCTURE


Cubic Symmetry
All cubic symmetry observed with
animal viruses is of the icosahedral
pattern, the most efficient
arrangement for subunits in a closed
shell
Helical Symmetry
protein subunits are bound in a periodic
way to the viral nucleic acid, winding it
into a helix; the filamentous viral
nucleic acid-protein complex
(nucleocapsid) is then coiled inside a
lipid-containing envelope

PRINCIPLES OF VIRUS STRUCTURE


Complex Structures
Some virus particles do not exhibit
simple cubic or helical symmetry
but are more complicated in
structure.

CHEMICAL COMPOSITION OF
VIRUSES
VIRAL PROTEIN
Facilitate transfer of the viral nucleic
acid from one host to another
Serve to protect the viral genome
against inactivation by nucleases
Participate in the attachment of the
virus particle to a susceptible cell
Provide structural symmetry of the
virus particle
Determines the antigenic
characteristics of the virus
Some viruses carry enzymes (which
are proteins) inside the virions

CHEMICAL COMPOSITION OF
VIRUSES
VIRAL NUCLEIC ACID
Viruses contain a SINGLE kind of
nucleic acid either DNA or RNA
that encodes the genetic information
necessary for replication of the virus.
The genome may be single-stranded
or double-stranded, circular or
linear, and segmented or
nonsegmented.
The type of nucleic acid, its
strandedness, and its size are major
characteristics used for classifying
viruses into families

CHEMICAL COMPOSITION OF
VIRUSES
VIRAL NUCLEIC ACID
Viral RNAs exist in several forms
may be a single linear molecule
(picornaviruses)
several segments of RNA that may
be loosely associated within the
virion (orthomyxoviruses)
The isolated RNA of viruses with
positive-sense genomes (ie,
picornaviruses, togaviruses) is
infectious, and the molecule
functions as an mRNA within the
infected cell

CHEMICAL COMPOSITION OF
VIRUSES
VIRAL NUCLEIC ACID
The isolated RNA of the negativesense RNA viruses, such as
rhabdoviruses and orthomyxoviruses,
is not infectious
The sequence and composition of
nucleotides of each viral nucleic acid
are distinctive. Many viral genomes
have been sequenced. The sequences
can reveal genetic relationships
among isolates

CHEMICAL COMPOSITION OF
VIRUSES
VIRAL NUCLEIC ACID
Viral nucleic acid may be
characterized by its G + C content.
DNA viral genomes can be analyzed
and compared using restriction
endonucleases, enzymes that cleave
DNA at specific nucleotide
sequences; each genome will yield a
characteristic pattern of DNA
fragments after cleavage with a
particular enzyme

CHEMICAL COMPOSITION OF
VIRUSES
VIRAL LIPID ENVELOPES
A number of different viruses contain
lipid envelopes as part of their
structure
The lipid is acquired when the viral
nucleocapsid buds through a cellular
membrane in the course of maturation

CHEMICAL COMPOSITION OF
VIRUSES
VIRAL GLYCOPROTEINS
Viral envelopes contain glycoproteins
In contrast to the lipids in viral
membranes, which are derived from
the host cell, the envelope
glycoproteins are virus-encoded.
the sugars added to viral glycoproteins
often reflect the host cell in which the
virus is grown

CHEMICAL COMPOSITION OF
VIRUSES
VIRAL GLYCOPROTEINS
It is the surface glycoproteins of an
enveloped virus that attach the virus
particle to a target cell by interacting
with a cellular receptor
often involved in the membrane fusion
step of infection
important viral antigens

CULTIVATION OF VIRUSES
Many viruses can be grown in cell cultures
or in fertile eggs under strictly controlled
conditions
Growth of virus in animals is still used for
the primary isolation of certain viruses and
for studies of the pathogenesis of viral
diseases and of viral oncogenesis.

The fundamental process of


viral infection is the viral
replicative cycle.

The cellular response to


that infection may
range
Hyperplasia
or cancer
Cytopathology
with
accompanying
cell death

No apparent
effect

Viral disease
Some harmful abnormality that results from viral
infection of the host organism.

Clinical disease
consists of overt signs and symptoms.

Syndrome
a specific group of signs and symptoms.

Inapparent (subclinical)
Viral infections that fail to produce any symptoms in
the host.

Important Features
of Acute Viral Diseases
Local Infections

Systemic Infections

Specific disease example

Respiratory (rhinovirus)

Measles

Site of pathology

Portal of entry

Distant site

Incubation period

Relatively short

Relatively long

Viremia

Absent

Present

Duration of immunity

Variablemay be short

Usually lifelong

Role of secretory antibody Usually important


(IgA) in resistance

Usually not important

Most viral infections do not result in


the production of disease.

Important principles that pertain to


viral disease include the following:
Many viral infections are subclinical.
The same disease may be produced by a variety of viruses.
The same virus may produce a variety of diseases.
The disease produced bears no relationship to viral morphology.

The outcome in any particular case is determined by both viral and


host factors and is influenced by the genetics of each.

Viral pathogenesis
The interaction of viral and host factors that leads
to disease production.

Disease pathogenesis subset of events


during an infection that results in disease
manifestation in the host
A virus is pathogenic for a particular host if it
can infect and cause signs of disease in that
host.
A strain of a certain virus is more virulent
than another strain if it commonly produces
more severe disease in a susceptible host.

Steps in viral pathogenesis


1.
2.
3.
4.
5.
6.

Entry into the host


Primary viral replication
Viral spread
Cellular injury
Host immune response
Viral clearance or establishment
of persistent infection
7. Viral shedding

Common Routes
of Viral Infection in Humans
Route of Entry

Virus Group

Respiratory tract

Parvovirus

Produce Local
Produce Generalized
Symptoms at Portal of Infection Plus Specific
Entry
Organ Disease
B19

Adenovirus

Most types

Herpesvirus

Epstein-Barr virus,
herpes simplex virus

Poxvirus
Picornavirus

Varicella virus
Smallpox virus

Rhinoviruses

Togavirus

Some enteroviruses
Rubella virus

Coronavirus

Most types

Orthomyxovirus

Influenza virus

Paramyxovirus

Parainfluenza viruses,
respiratory syncytial
virus

Mumps virus, measles


virus

Common Routes
of Viral Infection in Humans
Route of Entry

Virus Group

Mouth, intestinal tract Adenovirus


Herpesvirus

Produce Local
Produce Generalized
Symptoms at Portal of Infection Plus Specific
Entry
Organ Disease
Some types
Epstein-Barr virus,
herpes simplex virus

Picornavirus

Reovirus

Cytomegalovirus
Some enteroviruses,
including poliovirus and
hepatitis A virus

Rotaviruses

Common Routes
of Viral Infection in Humans
Route of Entry Virus Group

Produce Local
Symptoms at Portal
of Entry

Produce Generalized Infection Plus


Specific Organ Disease

Skin

Mild trauma

Injection

Bites

Papillomavirus

Most types

Herpesvirus

Herpes simplex virus

Poxvirus

Molluscum
contagiosum virus, orf
virus

Hepadnavirus

Hepatitis B

Herpesvirus

Epstein-Barr virus, cytomegalovirus

Retrovirus

Human immunodeficiency virus

Togavirus

Many species, including eastern


equine encephalitis virus
Many species, including yellow fever
virus

Flavivirus
Rhabdovirus

Entry & Primary Replication


Viruses usually replicate at the primary site of
entry.
Someproduce disease at the portal of entry
and have no necessity for further systemic
spread.

Many viruses produce disease at sites distant


from their point of entry
The most common route is via the
bloodstream or lymphatics.
Presence of virus in the blood -viremia
Virions may be free in the plasma or
associated with particular cell types
The viremic phase is short in many viral
infections.

Viruses tend to exhibit organ and cell


specificities tropism determines the
pattern of systemic illness produced during a
viral infection
Tissue & cell tropism by a given virus usually
reflect the presence of specific cell surface
receptors for that virus

Destruction of virus-infected cells in the target tissues


and physiologic alterations produced in the host by
the tissue injury are partly responsible for the
development of disease.
Some tissues
Can rapidly regenerate, such as intestinal epithelium.
Can withstand extensive damage better than others, such
as the brain.

Some physiologic effects may result from nonlethal


impairment of specialized functions of cells, such as
loss of hormone production.

General symptoms associated with many viral


infections, such as malaise and anorexia, may
result from host response functions such as
cytokine production.
Clinical illness is an insensitive indicator of
viral infection.
Inapparent infections by viruses are very
common.

The host either succumbs or


recovers from viral infection.

OR

Recovery mechanisms
Innate immune response
Adaptive immune responses

Interferon and other cytokines, humoral and


cell-mediated immunity, and possibly other
host defense factors are involved.
The relative importance of each component
differs with the virus and the disease.

In acute infections, recovery is associated


with viral clearance.
However, there are times when the host
remains persistently infected with the virus
(chronic or latent).

This is a necessary step to maintain a viral


infection in populations of hosts.
Shedding usually occurs from the body surfaces
involved in viral entry.
Shedding occurs at different stages of disease
depending on the particular agent involved.
It represents the time at which an infected
individual is infectious to contacts.
In some viral infections, such as rabies, humans
represent dead-end infections, shedding does
not occur.

Nonspecific host defense mechanisms are


usually elicited very soon after viral infection.
The most prominent among the innate
immune responses is the induction of
interferons.
These responses help inhibit viral growth during
the time it takes to induce specific humoral and
cell-mediated immunity.

Both humoral and cellular components of the


immune response are involved in control of viral
infections.
Viruses elicit a tissue response different from the
response to pathogenic bacteria.
Polymorphonuclear leukocytes form the principal
cellular response to the acute inflammation caused
by pyogenic bacteria.
Infiltration with mononuclear cells and lymphocytes
characterizes the inflammatory reaction of
uncomplicated viral lesions.

Virus-encoded proteins serve as targets for the immune


response.
Virus-infected cells may be lysed by cytotoxic T lymphocytes as
a result of recognition of viral polypeptides on the cell surface.

Humoral immunity protects the host against reinfection by


the same virus.
Neutralizing antibody directed against capsid proteins
blocks the initiation of viral infection, presumably at the
stage of attachment, entry, or uncoating.
Secretory IgA antibody
important in protecting against infection by viruses through the
respiratory or gastrointestinal tracts.

Viruses have evolved a variety of ways that serve to


suppress or evade the host immune response and
thus avoid being eradicated.

Infect cells of the immune system and abrogating their


function (HIV).
Infect neurons that express little or no class I MHC
(herpesvirus).
Encode immunomodulatory proteins that inhibit MHC
function (adenovirus, herpesvirus).
Inhibit cytokine activity (poxvirus, measles virus).
Mutate and change antigenic sites on virion proteins
(influenza virus, HIV).
Downregulate the level of expression of viral cell
surface proteins (herpesvirus).

Antiviral Chemotherapy
Interferons
Viral Vaccines

Limitations:
Antiviral agents must be capable of selectively
inhibiting viral functions without damaging the
host.
Many rounds of virus replication occur during the
incubation period and the virus has spread before
symptoms appear
making a drug relatively ineffective.

Can be used to treat established infections


when vaccines would not be effective.
Antivirals are needed to reduce morbidity and
economic loss due to viral infections and to
treat increasing numbers of
immunosuppressed patients who are at
increased risk of infection.

Examples of Antiviral Compounds


Used for Treatment of Viral Infections:
Viral Spectrum1

Drug

Nucleoside Analog

Mechanism of Action

Acyclovir

Yes

Viral polymerase inhibitor Herpes simplex, varicellazoster

Amantadine

No

Blocks viral uncoating

Cidofovir

No

Viral polymerase inhibitor Cytomegalovirus, herpes


simplex, polyomavirus

Didanosine (ddI)

Yes

Reverse transcriptase
inhibitor

Foscarnet

No

Viral polymerase inhibitor Herpesviruses, HIV-1, HBV

Fuzeon

No

HIV fusion inhibitor (blocks HIV-1


viral entry)

Ganciclovir

Yes

Viral polymerase inhibitor Cytomegalovirus

Indinavir

No

HIV protease inhibitor

HIV-1, HIV-2

Lamivudine (3TC)

Yes

Reverse transcriptase
inhibitor

HIV-1, HIV-2, HBV

Nevirapine

No

Reverse transcriptase
inhibitor

HIV-1

Influenza A

HIV-1, HIV-2

Examples of Antiviral Compounds


Used for Treatment of Viral Infections:
Viral Spectrum1

Drug

Nucleoside Analog

Mechanism of Action

Ribavirin

Yes

Perhaps blocks capping of Respiratory syncytial virus,


viral mRNA
influenza A and B, Lassa
fever, hepatitis C, others

Ritonavir

No

HIV protease inhibitor

HIV-1, HIV-2

Saquinavir

No

HIV protease inhibitor

HIV-1, HIV-2

Stavudine (d4T)

Yes

Reverse transcriptase
inhibitor

HIV-1, HIV-2

Trifluridine

Yes

Viral polymerase inhibitor Herpes simplex,


cytomegalovirus, vaccinia

Valacyclovir

Yes

Viral polymerase inhibitor Herpesviruses

Vidarabine

Yes

Viral polymerase inhibitor Herpesviruses, vaccinia,


HBV

Zalcitabine (ddC)

Yes

Reverse transcriptase
inhibitor

HIV-1, HIV-2, HBV

Zidovudine (AZT)

Yes

Reverse transcriptase
inhibitor

HIV-1, HIV-2, HTLV-1

Comprise the majority of available antiviral


agents.
MOA:
They inhibit nucleic acid replication by inhibition
of polymerases for nucleic acid replication.
Some analogs can be incorporated into the
nucleic acid and block further synthesis or alter its
function.
Analogs can inhibit cellular enzymes as well as
virus-encoded enzymes.

The most effective analogs are those able to


specifically inhibit virus-encoded enzymes, with
minimal inhibition of analogous host cell
enzymes.
Resistance:
Virus variants resistant to the drug usually arise over
time, sometimes quite rapidly.
The use of combinations of antiviral drugs can delay
the emergence of resistant variants (eg, "triple drug"
therapy used to treat HIV infections).

Examples of nucleoside analogs include


acyclovir (Acycloguanosine),
lamivudine (3TC),
ribavirin,
vidarabine (Adenine Arabinoside),
and zidovudine (azidothymidine; AZT).

Nucleotide analogs differ from nucleoside


analogs in having an attached phosphate
group.
Their ability to persist in cells for long periods
of time increases their potency.
Example:
Cidofovir (HPMPC)

Nevirapine was the first member of the class of


nonnucleoside reverse transcriptase inhibitors.
It does not require phosphorylation for activity
and does not compete with nucleoside
triphosphates.
MOA:
Bind directly to reverse transcriptase and disrupting
the enzyme's catalytic site.

Resistant mutants emerge rapidly.

Saquinavir
The first protease inhibitor to be approved for
treatment of HIV infection.

A peptidomimetic agent designed by


computer modeling as a molecule that fits
into the active site of the HIV protease
enzyme.

MOA
Inhibit the viral protease
that is required at the
late stage of the
replicative cycle

cleave the viral gag and


gag-pol polypeptide
precursors

activate the reverse


transcriptase that will be
used in the next round of
infection.

yields noninfectious virus


particles

form the mature virion


core

Protease inhibitors include


Indinavir
Ritonavir
etc

Fuzeon
a large peptide

MOA:
Blocks the virus and cellular membrane fusion
step involved in entry of HIV-1 into cells.

Amantadine and
Rimantadine
Foscarnet
(Phosphonoformic
Acid, PFA)

Methisazone

These synthetic amines specifically inhibit influenza A viruses by blocking


viral uncoating.
They must be administered prophylactically to have a significant
protective effect.

An organic analog of inorganic pyrophosphate


Selectively inhibits viral DNA polymerases and reverse transcriptases at
the pyrophosphate-binding site.

An inhibitor of poxviruses.
It was the first antiviral agent to be described and contributed to the
campaign to eradicate smallpox.
It blocked a late stage in viral replication, resulting in the formation of
immature, noninfectious virus particles.

Host-coded proteins that are members of the


large cytokine family and which inhibit viral
replication.
They are produced very quickly (within hours)
in response to viral infection or other
inducers.
Are one of the body's first responders in the
defense against viral infection.

Interferons are central to the innate antiviral


immune response.
Also modulate humoral and cellular
immunity.
Have broad cell growth regulatory activities.

Three general groups


IFN- type I (viral IFN)
The IFN- family is large, being coded by at least 20
genes in the human genome

IFN- type I (viral IFN)


IFN- type II (immune IFN)

** the IFN- and IFN- families are coded by


one gene each.

Properties of Human Interferons


Type
Property

Alpha

Beta

Gamma

Current nomenclature IFN-

IFN-

IFN-

Former designation

Leukocyte

Fibroblast

Immune interferon

Type designation

Type I

Type I

Type II

Number of genes that


code for family
Principal cell source

20

Most cell types

Most cell types

Lymphocytes

Inducing agent

Viruses; dsRNA

Viruses; dsRNA

Mitogens

Stability at pH 2.0

Stable

Stable

Labile

Glycosylated

No

Yes

Yes

Introns in genes

No

No

Yes

Homology with IFN-

8095%

30%

< 10%

Properties of Human Interferons


Type
Chromosomal location 9
of genes
Size of secreted protein 165
(number of amino
acids)
IFN receptor
IFNAR

12

166

143

IFNAR

IFNGR

Chromosomal location 21
of IFN receptor genes

21

The different interferons are similar in size,


but the three classes are antigenically distinct.
IFN- and IFN- are resistant to low pH.
IFN- and IFN- are glycosylated, but the
sugars are not necessary for biologic activity,
so cloned interferons produced in bacteria are
biologically active.

Dendritic cells
are potent interferon producers;
under the same virus challenge conditions,
dendritic cells can secrete up to 1000x more
interferon than fibroblasts.

Interferons are produced by all vertebrate species.


Normal cells do not generally synthesize interferon
until they are induced to do so.
Infection with viruses is a potent insult leading to
induction;
RNA viruses are stronger inducers of interferon than DNA
viruses.
Interferons also can be induced by double-stranded RNA,
bacterial endotoxin, and small molecules such as tilorone.

IFN-
not produced in response to most viruses but is induced
by mitogen stimulation.

IFN- and IFN-


synthesized by many cell types.

IFN-
produced mainly by lymphocytes, especially T cells
and natural killer (NK) cells.

Dendritic cells
are potent interferon producers;
under the same virus challenge conditions, dendritic
cells can secrete up to 1000x more interferon than
fibroblasts.

Interferon does not protect the virus-infected


cell that produces it, and interferon itself is
not the antiviral agent.
Rather, interferon moves to other cells where
it induces an antiviral state by prompting the
synthesis of other proteins that actually
inhibit viral replication. Interferon molecules
bind to specific cell surface receptors on
target cells.

Receptor binding triggers


tyrosine phosphorylation
and activation of
transcription factors (STAT
proteins) in the cytoplasm

Translocate into the nucleus


and mediate transcription
of interferon-inducible
genes (which occurs within
minutes after interferon
binding).

Synthesis of several
enzymes believed to be
instrumental in the
development of the
antiviral state.

Several pathways appear to be


involved:
A dsRNA-dependent protein kinase, PKR, which
phosphorylates and inactivates cellular initiation factor
eIF-2 and thus prevents formation of the initiation complex
needed for viral protein synthesis;
An oligonucleotide synthetase, 2-5A synthetase, which
activates a cellular endonuclease, RNase L, which in turn
degrades mRNA;
A phosphodiesterase, which inhibits peptide chain
elongation;
Nitric oxide synthetase, which is induced by IFN- in
macrophages. These explanations, however, fail to reveal
why the antiviral state acts selectively against viral mRNAs
and not cellular mRNAs.

Other steps in viral replication may also be


inhibited by interferon.

Interferons are almost always host speciesspecific in function but are not specific for a
given virus.
When interferon is added to cells prior to
infection, there is marked inhibition of viral
replication but nearly normal cell function.
Interferons are extremely potent, so that very
small amounts are required for function.
<50 molecules of interferon per cell are sufficient to
induce the antiviral state.

Specific viral proteins


May block induction of expression of interferon (herpesvirus,
papillomavirus, filovirus, hepatitis C virus, rotavirus);
May block the activation of the key PKR protein kinase
(adenovirus, herpesviruses);
May activate a cellular inhibitor of PKR (influenza,
poliovirus);
May block interferon-induced signal transduction
(adenovirus, herpesviruses, hepatitis B virus);
May neutralize IFN- by acting as a soluble interferon receptor
(myxoma virus).

The purpose of viral vaccines is to utilize the


immune response of the host to prevent viral
disease.
Vaccination is the most cost-effective method
of prevention of serious viral infections.

Immunity to viral infection is based on the


development of an immune response to specific
antigens located on the surface of virus particles or
virus-infected cells.
For enveloped viruses, the important antigens are the
surface glycoproteins.
Although infected animals may develop antibodies
against virion core proteins or nonstructural proteins
involved in viral replication, that immune response is
believed to play little or no role in the development of
resistance to infection.

The pathogenesis of a particular viral infection


influences the objectives of immunoprophylaxis.
Mucosal immunity (local IgA)
is important in resistance to infection by viruses that
replicate exclusively in mucosal membranes (rhinoviruses,
influenza viruses, rotaviruses).

Viruses that have a viremic mode of spread (polio,


hepatitis, measles)
are controlled by serum antibodies.

Cell-mediated immunity also is involved in protection


against systemic infections (measles, herpes).

Killed-Virus Vaccines
Attenuated Live-Virus
Vaccines

Made by purifying viral preparations to a


certain extent and then inactivating viral
infectivity in a way that does minimal damage
to the viral structural proteins
Mild formalin treatment is frequently used.

Advantages
There is no reversion to
virulence by the vaccine virus
and that vaccines can be
made when no acceptable
attenuated virus is available.

Disadvantages
Extreme care is required in their manufacture to
make certain that no residual live virulent virus is
present in the vaccine.
The immunity conferred is often brief and must be
boosted, which not only involves the logistic
problem of repeatedly reaching the persons in need
of immunization but also has caused concern about
the possible effects (hypersensitivity reactions) of
repeated administration of foreign proteins.

Disadvantages
Parenteral administration of killed-virus
vaccine, even when it stimulates circulating
antibody (IgM, IgG) to satisfactory levels, has
sometimes given limited protection because
local resistance (IgA) is not induced adequately
at the natural portal of entry or primary site of
multiplication of the wild virus infectioneg,
nasopharynx for respiratory viruses, alimentary
tract for poliovirus

Disadvantages
The cell-mediated response to
inactivated vaccines is generally poor.
Some killed-virus vaccines have induced
hypersensitivity to subsequent infection,
perhaps owing to an unbalanced immune
response to viral surface antigens that
fails to mimic infection with natural virus.

Utilize virus mutants that antigenically


overlap with wild-type virus but are restricted
in some step in the pathogenesis of disease.

Advantage
Act like the natural infection with regard to
their effect on immunity.
They multiply in the host and tend to
stimulate longer-lasting antibody
production, to induce a good cell-mediated
response, and to induce antibody
production and resistance at the portal of
entry.

Disadvantages
The risk of reversion to greater virulence during multiplication
within the vaccinee. Although reversion has not proved to be a
problem in practice, its potential exists.
Unrecognized adventitious agents latently infecting the culture
substrate (eggs, primary cell cultures) may enter the vaccine
stocks. Viruses found in vaccines have included avian leukosis
virus, simian polyomavirus SV40, and simian cytomegalovirus.
The problem of adventitious contaminants may be circumvented
through the use of normal cells serially propagated in culture
(eg, human diploid cell lines) as substrates for cultivation of
vaccine viruses.

Disadvantages
The storage and limited shelf life of attenuated
vaccines present problems, but this can be overcome
in some cases by the use of viral stabilizers (eg, MgCl2
for poliovaccine).
Interference by coinfection with a naturally occurring,
wild-type virus may inhibit replication of the vaccine
virus and decrease its effectiveness. This has been
noted with the vaccine strains of poliovirus, which can
be inhibited by concurrent infections by various
enteroviruses.

You might also like