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MM 526-541 and 145-152

Table of Contents



1.    To provide an awareness of the mode of action and potential clinical use of interferon.

2.    To provide insight into the uses and misuses of antiviral vaccines.

3.    To develop the concept of viral-mediated interference with viral replication.

4.    To relate the lysogenic state to diseases thought to be caused by "dormant," "latent" or "slow" viruses.

5.    To define the rational use of antiviral agents.

6.    To gain familiarity with the structure and function of antiviral drugs.

Specific educational objectives (terms and concepts upon which you will be tested)

Discussion of Interference

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 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- a = a - Interferon (20 subtypes) - from many different cell types
IFN - b = b - Interferon (2 subtypes) - from fibroblasts, macrophages
IFN -g  = g - Interferon (3 subtypes) - from T-lymphocytes


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 - g is much greater than that of IFN - a or IFN - b . Effects of interferon on the functions of the uninfected 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.


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.

Principal vaccines used in prevention of viral diseases of humans

Immunization Recommended for General Public
Source of Vaccine
Condition of Virus
Route of Administration
Poliomyelitis Tissue culture (human diploid cell line, monkey kidney) Live attenuated




Measles Tissue culture (chick embryo) Live attenuated Subcutaneous
Mumps Tissue culture (chick embryo) Live attenuated Subcutaneous
Rubella Tissue culture (duck embryo, rabbit, or human diploid ) Live attenuated Subcutaneous
Hepatitis type B Purified HBsAg from "healthy" carriers; HBsAg from recombinant DNA in yeast Subunit Subcutaneous
Chickenpox/Zoster Tissue culture Live attenuated Subcutaneous


Immunization Recommended Only Under Certain Conditions
(Epidemics, Exposure, Travel, Military)
Source of Vaccine
Condition of Virus
Route of Administration
Smallpox 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 A Tissue culture Killed 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
Adenovirus Human diploid cell cultures Live attenuated Oral, by enteric-coated capsule
Japanese B encephalitis Mouse brain (formalinized), tissue culture Killed Subcutaneous
Venezuelan equine encephalomyelitis Guinea pig heart cell culture Live attenuated Subcutaneous
Eastern equine encephalomyelitis Chick embryo cell culture Killed Subcutaneous
Western equine encephalomyelitis Chick embryo cell culture Killed Subcutaneous
Russian spring-summer encephalitis Mouse brain (formalinized Killed Subcutaneous

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:

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: 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: 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:

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)

2.    Valacyclovir (Valtrex)

        This is the L-valyl ester of acyclovir.  It has the same spectrum of activity as acyclovir.

3.    Adenine arabinoside (Ara A) (Vidarabine)

Structre of Adenine arabinoside

4.    Cytosine arabinoside (Ara C)

5.    Iododeoxyuridine (Idoxuridine) 6.    Trifluorothymidine (Trifluridine) 7.    Foscarnet Sodium (Phosphonoformic acid)

8.    Ganciclovir (Cytovene)

9.    Fomivirsen (Vitravene)
This drug was approved by the U.S. Food and Drug Administration in 1998 for the treatment of cytomegalovirus retinitis. It is unique in that it is the first "antisense" antiviral approved by the FDA.  An "antisense" vaccine is one which is a single-stranded DNA complement to a mRNA.  The DNA and mRNA bind to each other and prevent the translation process.  It is administered directly into the eye.
10.    Amantadine 11.    Rimantadine 12.    Isatin- b-Thiosemicarbazone (Methisazone) 13.    N-methyl-isatin-b -Thiosemicarbazone (Marburan) 14.    Alpha interferon 15.    Ribavirin (Virazole) 16.    Azidothymidine (AZT, Zidovudine, Retrovir)
17.    Dideoxyinosine (ddI) (Videx)


18.    Dideoxycytidine (ddC)

19.    Lamivudine - 3TC (Epivir)

20.    Stavudine, d4T

 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 that inhibits reverse transcriptase.

21.    Delavirdine
This is a nonnucleoside inhibitor of reverse transcriptase.


22.    Nevirapine
This is a nonnucleoside inhibitor of reverse transcriptase.

23.    Saquinavir (Invirase) (Hoffman - LaRoche) 24.    Ritonavir (Norvir (Abbott) 25.    Indinavir (Crixivan) (Merck) 26.    Viracept (Agouron Pharmaceuticals)


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:

        B.     Cytomegalovirus infection         C.     Influenza A virus infection         D.     Smallpox virus infection         E.     Papilloma virus infection (genital warts)         F.     Lassa fever virus, respiratory syncytial disease virus,
                MuertoCanyon fever virus         G.     Human immunodeficiency virus (HIV)
 Azidothymidine (AZT)
 Dideoxyinosine (ddI)
Dideoxycytosine (ddC)
Lamivudine - 3TC
Stavudine, d4T

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