The
physician's job is to interfere with viral replication in order to prevent
or ameliorate the disease process. This can be done by manipulating the
biological system of the patient or by utilizing antiviral antibiotics.
In general, the more complex a system is (such as the viral replication
cycle), the more easily that system is disrupted. However, in viral replication,
the virus is utilizing mostly host cell protein-synthesizing systems. Disruption
of the viral replication cycle can also affect cellular metabolism in not
only the infected cell but also in the noninfected cell. However, there
are ways to interfere with viral replication with minimal effect on the
host cell.
Interferon
Interferon
is a class of glycoproteins which interferes with virus replication. There
are numerous types of interferon and each is produced by an animal or by
cultured animal cells. Interferon synthesis is induced by viruses or by
certain biochemicals and can be of three types:
IFN-alpha
=alpha -Interferon (20 subtypes)
- from many different cell types
IFN
-gamma =gamma - Interferon (3 subtypes) - from T-lymphocytes
Characteristics
a.
Interferons are cell specific in both their production and their effects.
b.
Interferons are virus non-specific.
c.
Interferons are induced by viruses, chemicals, some species of bacteria
and some extracts of fungi.
d.
Although all animal cells appear able to produce one or more types of interferon,
cells of the bone marrow, spleen, and macrophages, appear to play a special
role, i.e., they produce a larger volume of interferon and a more potent
interferon.
Induction
of interferon
The
nature of the stimulus to interferon production has been clarified by the
discovery that double-stranded RNAs, such as reovirus RNA and certain synthetic
polynucleotides, can induce a large production of interferon in many animals
and in tissue cultures.
For
most RNA viruses, double-stranded RNA segments produced during replication
mediate the induction of interferon.
Production
of interferon
In
virus-infected cells, the synthesis of interferon begins after viral maturation
is initiated and then continues for many hours.
Interferons
are synthesized on membrane-bound polysomes. As they are formed, they are
segregated into vesicles and are glycosylated; from the vesicles they are
excreted outside the cells. Therefore until they are excreted, interferons
do not act on the cell that produces them.
Mechanism
of interferon action
Suggested
mechanisms for the antiviral action of interferon.
Interferons
cause antiviral resistance not directly, but by activating cellular genes
for antiviral proteins; they are ineffective in enucleated cytoplasts or
in the presence of actinomycin D.
Interferons
induce the cell response by interacting with the cell surface. At the cell
surface, interferons bind to receptors containing gangliosides (glycosylated
phospholipids); transformed cells, which are deficient in gangliosides,
are less interferon-sensitive than normal cells. In human cells, genes
specifying the receptors are present on chromatosome 21; 21-trisomic (Down's
syndrome) cells are especially sensitive to interferon. The molecular mechanisms
of interferon-induced anti-viral resistance are multiple, and probably
differ in different cell-virus systems. However, in vitro studies with
extracts of interferon-treated cells show that the main target of interferon
action is translation, which is blocked by two mechanisms, involving a
protein kinase and a nuclease. In both, the block requires the presence
of minute amounts of double-stranded RNA (dsRNA), which seems to signal
to the cells the presence of a viral infection. (As in the induction of
interferon, the dsRNA may be that of a viral replicative intermediate,
or it may result from symmetric transcription of the viral DNA). Both translation
blocks are therefore specific for virus-infected cells (containing dsRNA),
although they do not distinguish cellular and viral messengers within such
cells.
Interferons
exhibit a wide variety of cell regulatory activities. They can be considered
a family of hormones involved in regulation of cell growth and differentiation.
The cell regulatory activity of IFN - is much greater than that of IFN
- alpha or IFN -beta . Effects of interferon on the functions of the uninfected
cells:
a.
Inhibition of cell replication;
b.
Inhibition of activation of spleen lymphocytes;
c.
Inhibition of liver regeneration;
d.
Inhibition of production of platelets and leukocytes;
e.
Enhancement of the expression of histocompatibility antigens on the lymphocyte
surface;
f.
Induction of liver degeneration;
g.
Reduction of antiviral antibody production by inhibition of B-cell activity;
h.
Enhancement of T-cell activity; and
i.
Increase in the cytotoxic activity of natural killer cells against virus-infected
cells.
These
effects denote a shift from humoral to cell-mediated immunity, which has
a defensive role in many viral infections, but a pathogenic role in some.
The combination of cell growth inhibition and enhancement of cell-mediated
immunity accounts for the antitumor effect of interferon in experimental
animals.
Vaccination
Viral
vaccination refers to the administration of virus (inactivated or live),
viral protein or antibody to a virus to a patient. Neither vaccination
nor recovery from natural infection always results in total protection
against a later infection with the same virus - REMEMBER THAT THE ANTIGENIC
DETERMINANTS OF AN ENVELOPED VIRUS CAN VARY WITH THE TYPE OF CELL IN WHICH
THE VIRUS GREW. Control is achieved by limiting the multiplication of virulent
virus upon subsequent exposure and preventing its spread to target organs
where the pathologic damage is done.
Immunization
Recommended for General Public
Diseases
Source of Vaccine
Condition of
Virus
Route of Administration
Rubella1,4
Tissue culture (duck embryo, rabbit, or human
diploid)
Immunization
Recommended Only Under Certain Conditions (Epidemics, Exposure,
Travel, Military)
Diseases
Source of Vaccine
Condition of
Virus
Route of Administration
Smallpox5
Lymph from calf or sheep (glycerolated, lyophilized)
Chorioallantois, tissue cultures (lyophilized)
Live vaccinia
Intradermal: multiple pressure, multiple
puncture
Yellow Fever
Tissue cultures and eggs (17D strain)
Live attenuated
Subcutaneous or intradermal
Hepatitis type B
Purified HBsAg from "healthy" carriers; HBsAg
from recombinant DNA in yeast
Subunit
Subcutaneous
Influenza
Highly purified or subunit forms of chick
embryo allantoic fluid (formalinized or UV-irradiated)
Killed
Subcutaneous or intradermal
Rabies
Duck embryo or human diploid cells
Killed
Subcutaneous
Adenovirus6
Human diploid cell cultures
Live attenuated
Oral, by enteric-coated capsule
Japanese B encephalitis7
Mouse brain (formalinized), tissue culture
Killed
Subcutaneous
Venezuelan equine encephalomyelitis8
Guinea pig heart cell culture
Live attenuated
Subcutaneous
Eastern equine encephalomyelitis7
Chick embryo cell culture
Killed
Subcutaneous
Western equine encephalomyelitis7
Chick embryo cell culture
Killed
Subcutaneous
Russian spring-summer encephalitis7
Mouse brain (formalinized
Killed
Subcutaneous
1 Available also as combined vaccines.
2Killed measles vaccine was available
for a short period. However, a serious delayed hypersensitivity reaction
sometimes occurred when children who had received primary immunization
with killed measles vaccine were later exposed to live measles virus. Because
of this complication, killed measles vaccine is no longer used.
3With less attenuated strains,
immune globulin USP is given in another limb at the time of vaccination.
4Neither monovalent rubella vaccine
nor combination vaccines incorporating rubella should be administered to
a postpubertal susceptible woman unless she is not pregnant and understands
that it is imperative not to become pregnant for at least 3 months after
vaccination. (The time immediately postpartum has been suggested as a safe
period for vaccination.)
5Since smallpox virus has been
totally eradicated from the world, vaccination is no longer recommended.
However, stocks of vaccine are held in depots if cases should reappear.
6Licensed but recommended only
for military populations in which epidemic respiratory disease caused by
adenovirus is a frequent occurrence. Types 4 and 7 are available as vaccines.
7Not available in the USA except
for the armed forces or for investigative purposes.
8Available for use in domestic
animals (from the US Department of Agriculture) and for investigative purposes.
Inactivated
virus vaccines - Inactivated vaccines generally
stimulate the development of circulating antibody against the capsid or
envelope proteins of the virus, conferring some degree of resistance. However,
there are disadvantages to this type of vaccine:
a.
Extreme care is required in their manufacture to make certain that no residual
live virulent virus is present in the vaccine;
b.
The immunity conferred is often brief and directed against only external
antigens (capsid, envelope, spike); c. Parenteral administration of inactivated
vaccine sometimes gives limited protection because local resistance is
not induced adequately at the natural port of entry or primary site of
multiplication of the wild virus infection; and
d.
Some inactivated virus vaccines induce hypersensitivity to subsequent infection
or booster shots.
Live
attenuated virus vaccines. An attenuated virus
is one which has lost its virulence or pathogenicity. This is usually accomplished
by passing the virus through an animal host. A vaccine made with an attenuated
virus has the advantage of acting like the natural infection with regard
to its effect on immunity. The viruses multiply in the host and tend to
stimulate longer-lasting antibody, antibody directed against all antigens
of the virus (including internal antigens), and resistance at the portal
of entry. The disadvantages of live attenuated vaccines include:
a.
The risk of reversion to greater virulence during multiplication within
the host;
b.
Unrecognized adventitious agents latently infecting the culture substrate
may enter the vaccine stocks; and
c.
Limited shelf life.
Recombinant
vaccines. These are live virus vaccines where the virus used has been altered
via genetic engineering to produce an avirulent but immune organism. This
is done in one of two ways:
a.
The virus normally causing a disease is attenuated by deleting one or more
of the genes required for virulence. This deletion may partially inactivate
the virus but it is still able to reproduce; and
b.
A virus that is not pathogenic, e.g., the vaccinia virus, is altered by
the insertion of a gene from a pathogenic virus. The inserted gene codes
for protein (e.g., the capsid protein) which elicits an immune reaction
and protects against the pathogenic virus.
Purified
protein vaccines. Viral genes are cloned into plasmids. That cloned DNA
is then transformed into a bacterial cell where it can be expressed if
appropriate genetic engineering techniques are used. As the bacterial cell
grows and reproduces, it synthesizes large quantities of the cloned protein.
The protein is purified and then used as a vaccine.
DNA
vaccines (gene vaccines). Viral DNA is inserted into human cells where
it codes for proteins that are expressed on the surface of the human cell,
thus stimulating the immune system. C. Lysogenization, latency, dormancy.
Normally when a virus enters a cell, it reproduces at a rapid rate and
produces large numbers of progeny virus. In rare cases, the virus enters
the cell and persists in the cell with little or no detectable effect on
the host cell. This is gusually called a latent or dormant infection. These
latent infections are sometimes activated by systemic shock. The basis
for this latency
has been attributed to:
1.
Lysogenization;
2.
Lack of pathogenicity of the virus; and
3.
Suppression of reproduction by the immune system (humoral, cell mediated,
interferon).
Antiviral
agents. Because of the great variability among
the reproductive cycles of viruses, it has not yet been possible to develop
a broad spectrum anti-viral compound. However, there are a few narrow spectrum
chemotherapeutic agents approved for the treatment of viral diseases.
1.
Acycloguanosine (Acyclovir) (Zovirax)
This
drug is used to treat herpesvirus skin infections. It inhibits viral DNA-dependent
DNA polymerase activity.
2.
Adenine arabinoside (Ara A) (Vidarabine)
This
drug is used to treat herpesvirus eye infections, encephalitis, neonatal
herpes, and herpes skin infections. It inhibits DNA polymerase.
3.
Cytosine arabinoside (Ara C)
This
drug is used to treat herpesvirus eye infections. It acts as an analog
of deoxy-cytidine and thus inhibits DNA synthesis.
Licensed
only as an anti-tumor drug.
4.
Iododeoxyuridine (Idoxuridine)
This
is an analog of thymidine and works by inhibiting DNA replication and transcription.
It is used topically against herpesvirus keratitis.
5.
Trifluorothymidine (Trifluridine)
This
is a deoxyribonucleoside analog which inhibits viral DNA replication and
transcription. It is used to treat herpes simplex keratitis.
6.
Foscarnet Sodium (Phosphonoformic acid)
This
drug is used to treat retinitis of cyto-megalovirus etiology.
7.
Ganciclovir (Cytovene)
This
drug is used to treat all types of cytomegalovirus infections in AIDS patients.
Because of bone marrow toxicity, its use is limited to AIDS patients. It
inhibits viral DNA polymerase.
8.
Amantadine
This
drug is used to treat influenza A. It interferes with penetration and/or
uncoating of the virus.
9.
Rimantadine
This
is a structural analog of amantadine. It inhibits penetration, uncoating
and release of the influenza A virus.
10.
Isatin- -Thiosemicarbazone (Methisazone)
This
drug is used to treat smallpox (a poxvirus disease) where it acts by inhibiting
translation of late mRNA.
This
is a methylated derivative of methisazone. It inhibits the translation
of late messenger RNA of the smallpox virus.
12.
Alpha interferon
This
compound inhibits viral protein synthesis (translation) via phosphorylation
of elongation factor 2 and/or induction of a ribonuclease which degrades
mRNA. It is used to treat condylomata acuminata (genital warts).
13.
Ribavirin (Virazole)
This
drug is used to treat Lassa fever, respiratory syncytial disease and Hanta
virus respiratory/renal disease (Muerto Canyon fever). It interferes with
the synthesis of viral mRNA by inhibiting DNA-dependent RNA polymerase,
inosine monophosphate dehydrogenase and various viral GTP-dependent enzymes.
It has the broadest spectrum of activity of any of the anti-viral compounds.
14.
Azidothymidine (AZT, Zidovudine, Retrovir)
This
drug is used to treat AIDS. It is a thymidine analog. It interferes with
viral RNA dependent DNA polymerase (reverse transcriptase).
A
chain terminator activated via phosphorylation by thymidine kinase.
15.
Dideoxyinosine (ddI) (Videx)
This
drug is used to treat AIDS. It is a nucleoside analog that is converted
to dideoxyadenosine triphosphate to inhibit the reverse transcriptase of
the human immunodeficiency virus.
16.
Dideoxycytidine (ddC)
This
drug is used to treat AIDS. It is a nucleoside analog that is converted
to dideoxycytidine triphosphate to inhibit the reverse transcriptase of
the human immuno-deficiency virus.
17.
Lamivudine - 3TC (Epivir)
This
drug is used to treat AIDS, but it can only be used in combination with
AZT and a protease inhibitor in patients who have never been treated previously
with AZT. It is a nucleoside analog.
18.
Saquinavir (Invirase) (Hoffman - LaRoche)
This
drug is used to treat AIDS, but it can only be used in combination with
AZT and Lamivudine - 3TC in patients who have never been treated previously
with AZT. It is a protease inhibitor.
19.
Ritonavir (Norvir (Abbott)
This
drug is used to treat AIDS, but it can only be used in combination with
AZT and Lamivudine - 3TC in patients who have never been treated previously
with AZT. It is a protease inhibitor.
20.
Indinavir (Crixivan) (Merck)
This
drug is used to treat AIDS, but it can only be used in combination with
AZT and Lamivudine - 3TC in patients who have never been treated previously
with AZT. It is a protease inhibitor.
21.
Viracept (Agouron Pharmaceuticals)
This
drug is used to treat aids, but it can only be used on combination with
AZT and Lamivudine - 3TC in patients who have never been previously treated
with AZT. It is the only protease inhibitor approved for children as well
as for adults.
Summary
1.
When human cells become infected by a virus, they may produce interferon.
Interferon is a class of glycoproteins which interfere with viral replication
by inducing the synthesis of a translation inhibitory protein and a nuclease.
2.
The induction of interferon is mediated by double-stranded RNA.
3.
In uninfected cells interferons act like a family of hormones involved
in regulation of cell growth and differentiation where they often effect
a shift from humoral to cell-mediated immunity.
4.
Effective vaccination for viral disease can be achieved using live viruses,
inactivated viruses, viral antigens or antibody directed against viruses.
5.
Pediatric patients are routinely immunized against the viral diseases of
polio, measles (rubeola), mumps and rubella. Several other viral vaccines
are available for special situations.
6.
In general the live attenuated viral vaccines induce the broadest range
of immunity (i.e., stimulate IgA, IgG and IgM production) and give the
longest acting immunity.
7.
Some viruses have the ability to be dormant or latent in a cell during
which time they do not reproduce themselves. Most commonly they do this
by integrating their DNA into the host cell DNA.
8.
The antiviral agents currently available are narrow spectrum compounds,
most of which are analogs of the purine or pyrimidine bases of DNA or RNA.
9.
The antiviral drugs and the diseases they are effective against are:
PreviousLecture 
Home 
NextLecture
Topof
lecture 