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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 lipd-
containing 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 virus-
specific 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 severe hemorrhagic
Ebola virus 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 negative-
sense 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 Usually not important
(IgA) in resistance
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. Entry into the host
2. Primary viral replication
3. Viral spread
4. Cellular injury
5. Host immune response
6. Viral clearance or establishment
of persistent infection
7. Viral shedding
Common Routes
of Viral Infection in Humans
Route of Entry Virus Group Produce Local Produce Generalized
Symptoms at Portal of Infection Plus Specific
Entry Organ Disease
Respiratory tract Parvovirus B19
Adenovirus Most types
Herpesvirus Epstein-Barr virus, Varicella virus
herpes simplex virus
Poxvirus Smallpox virus
Picornavirus Rhinoviruses Some enteroviruses
Togavirus Rubella virus
Coronavirus Most types
Orthomyxovirus Influenza virus
Paramyxovirus Parainfluenza viruses, Mumps virus, measles
respiratory syncytial virus
virus
Common Routes
of Viral Infection in Humans
Route of Entry Virus Group Produce Local Produce Generalized
Symptoms at Portal of Infection Plus Specific
Entry Organ Disease
Mouth, intestinal tract Adenovirus Some types
Herpesvirus Epstein-Barr virus, Cytomegalovirus
herpes simplex virus
Picornavirus Some enteroviruses,
including poliovirus and
hepatitis A virus
Reovirus Rotaviruses
Common Routes
of Viral Infection in Humans
Route of Entry Virus Group Produce Local Produce Generalized Infection Plus
Symptoms at Portal Specific Organ Disease
of Entry
Skin
Mild trauma Papillomavirus Most types
Herpesvirus Herpes simplex virus
Poxvirus Molluscum
contagiosum virus, orf
virus
Injection Hepadnavirus Hepatitis B
Herpesvirus Epstein-Barr virus, cytomegalovirus
Retrovirus Human immunodeficiency virus
Bites Togavirus Many species, including eastern
equine encephalitis virus
Flavivirus Many species, including yellow fever
virus
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:
Drug Nucleoside Analog Mechanism of Action Viral Spectrum1

Acyclovir Yes Viral polymerase inhibitor Herpes simplex, varicella-


zoster
Amantadine No Blocks viral uncoating Influenza A

Cidofovir No Viral polymerase inhibitor Cytomegalovirus, herpes


simplex, polyomavirus
Didanosine (ddI) Yes Reverse transcriptase HIV-1, HIV-2
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 HIV-1, HIV-2, HBV


inhibitor
Nevirapine No Reverse transcriptase HIV-1
inhibitor
Examples of Antiviral Compounds
Used for Treatment of Viral Infections:
Drug Nucleoside Analog Mechanism of Action Viral Spectrum1

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 HIV-1, HIV-2


inhibitor
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 HIV-1, HIV-2, HBV
inhibitor
Zidovudine (AZT) Yes Reverse transcriptase HIV-1, HIV-2, HTLV-1
inhibitor
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


cleave the viral gag and
that is required at the form the mature virion
gag-pol polypeptide
late stage of the core
precursors
replicative cycle

activate the reverse


transcriptase that will be yields noninfectious virus
used in the next round of particles
infection.
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.
These synthetic amines specifically inhibit influenza A viruses by blocking
Amantadine and viral uncoating.
Rimantadine They must be administered prophylactically to have a significant
protective effect.

Foscarnet An organic analog of inorganic pyrophosphate


(Phosphonoformic Selectively inhibits viral DNA polymerases and reverse transcriptases at
the pyrophosphate-binding site.
Acid, PFA)

An inhibitor of poxviruses.
It was the first antiviral agent to be described and contributed to the
Methisazone 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 20 1 1
code for family
Principal cell source 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 9 12
of genes
Size of secreted protein 165 166 143
(number of amino
acids)
IFN receptor IFNAR IFNAR IFNGR
Chromosomal location 21 21 6
of IFN receptor genes
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.
Translocate into the nucleus
Receptor binding triggers Synthesis of several
and mediate transcription
tyrosine phosphorylation enzymes believed to be
of interferon-inducible
and activation of instrumental in the
genes (which occurs within
transcription factors (STAT development of the
minutes after interferon
proteins) in the cytoplasm antiviral state.
binding).
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 species-
specific 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.