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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:
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
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
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.