1. Virus-Host Interactions: Viral Infections
Virus-host interactions may be considered at different levels;
the cell, the individual and the community
At the cellular level, viral infection may cause a broad spectrum
of effects
a) Cytocidal effect
b) Cellular proliferation
c) Steady state infection
2. Cellular injury may be due to a number of causes
1) Early or nonstructural viral proteins often cause a shut-down
of host protein and DNA synthesis
2) Large amounts of viral macromolecules that accumulate in
the infected cell may distort the cellular architecture and exert
a toxic effect
3) The permeability of plasma membranes may be altered
4) Many viruses produce alterations in the cytoplasmic membrane
of infected cells
5) Certain viruses cause damage to the chromosomes of host cells
(eg: measles, mumps, adenovirus, varicella, cytomegaloviruses)
3. Inclusion bodies
Virus-specific intracellular globular masses which are produced during
replication of virus in host cells
They can be demonstrated in virus infected cells under light
-microscope after fixation and staining
They may be present in the cytoplasm (rabies virus), nucleus
(herpes virus) or both (measles virus)
Intracytoplasmic inclusions are found in cells infected with
rabies virus (Negri bodies), vaccinia (Guarnieri bodies), molluscum
contagiosum (molluscum bodies) and fowl pox (Bollinger bodies)
Intranuclear inclusions were classified into two types by Cowdry (1934)
Cowdry type A includes inclusion bodies of variable size and granular
appearance (eg: herpes virus, yellow fever virus) and type B inclusions
are more circumscribed and multiple (eg: adenovirus, poliovirus)
4. Demonstration of inclusion bodies helps in the diagnosis of some
viral infections (Negribodies: presumptive diagnosis of rabies)
Cytoplasmic inclusion body caused by rabies virus in
brain tissue
5. Pathogenesis of viral infections
Depending on the clinical outcome, viral infections can be classified as
1. Inapparent (subclinical)
2. Apparent (clinical or overt)
a) acute b) subacute c) chronic
Latent infections
Herpes simplex and varicella-zoster viruses remain latent in nerve
root ganglia, to be reactivated periodically
HBV and HIV infections
Slow viral diseases
6. Viruses enter the body through the following routes
1. Respiratory tract
2. Alimentary tract
3. Skin
4. Genital tract
5. Conjunctiva
6. Congenital
7. Routes of transmission of viral infections
Route of
transmission
Viruses
Respiratory tract
Influenza, Parainfluenza, RSV, Measles,
Mumps, Rubella, Rhinovirus, Adenovirus
Coronavirus,Varicella-zoster, CMV, EBV
Alimentary tract
Poliovirus, Adenovirus, Hepatitis A, E
viruses, Rotavirus, Norwalk virus
Skin
Herpes simplex, Papilloma viruses
Molluscum contagiosum, Rabies virus
Arboviruses, HBV, HCV, HIV, HTLV
Genital tract
Herpes simplex viruses, HBV, HCV
HIV, Papillomaviruses
Conjunctiva
Some adenoviruses,
Few enteroviruses
8. Congenital infection
Many viruses are transmitted vertically from parent to progeny
Congenital infection may occur at any stage from the development
of the ovum up to birth
In acute systemic infections, congenital infection usually leads
to fetal death and abortion
Rubella and cytomegalovirus produce maldevelopment or severe
neonatal disease
HIV, HSV, many tumor viruses cause congenital infection
11. Incubation period
It is the time taken for the virus to spread from the site of entry to the
target organs for the production of lesions
Its duration is therefore influenced by the relation between the site of
entry, multiplication and lesion
The incubation period in HBV may be 2-6 months and in slow viral
infections, many years
Papillomas and molluscum contagiosum have long incubation periods,
probably because the viruses multiply slowly
14. Non-specific responses
1. Age
Most of the viral infections tend to
be more serious at extremes of life
Rotaviruses cause severe disease
only in infants
15. 2. Hormones
Corticosteroids administration enhances most viral infections
The particularly severe course of many viral infections in pregnancy
may be related to the hormonal changes
3. Malnutrition
Malnutrition interferes with the humoral and cell-mediated immune
responses, therefore it can exacerbate viral infections
(eg: measles – higher incidence of complications and a higher case
fatality rate in malnourished children)
4. Body temperature
Fever may act as a natural defence mechanism against viral infections
as most viruses are inhibited by temperatures above 390C
16. 5. Phagocytosis
Macrophages phagocytose viruses and are important in clearing
viruses from blood stream
Polymorphonuclear leucocytes do not play any significant role
6. Interferons
Interferons are a family of glycoproteins produced by cells on
induction by viral or nonviral inducers
Interferon by itself has no direct action on viruses but acts on other
cells of the same species, rendering them refractory to viral infection
On exposure to interferon, cells produce a protein (translation
inhibiting protein, TIP) which selectively inhibits translation of
viral mRNA
17. Types of interferons
They are classified into three types
1. IFN-α
It is induced by virus infection and produced by leucocytes
It has antiviral activity
2. IFN-β
It is also induced by virus infection but produced by fibroblasts and
epithelial cells
It also has antiviral activity
18. 3. IFN-γ
Produced by T-lymphocytes and NK cells, on stimulation by antigens
or mitogens
It is a lymphokine with immunoregulatory functions
It enhances MHC antigens and activates cytotoxic T-lymphocytes,
macrophages and NK cells
Modulates antibody formation and supresses DTH
Mechanism of action
IFN-α and IFN-β induce the production of three enzymes namely
protein kinase, an oligonucletide synthetase and an RNaseL. This
leads to inhibition of viral protein synthesis but does not affect host
protein synthesis
19. Immunological responses
1. Antibody-mediated immunity
IgG, IgM, IgA antibodies are produced in response to virus infection
IgG and IgM play a major role in blood and tissue spaces while IgA
is more important in mucosal surfaces
IgA is important in resistance to infection of the respiratory, intestinal
and urogenital tracts
20. Antibodies may act in the following ways
Neutralisation of virus which prevents attachment, penetration
or subsequent events
Antibody may attach to viral antigens on the surface of infected cells,
rendering these cells prone to lysis by complement or destruction by
phagocytes or killer lymphocytes
Immune opsonisation of virus for phagocytosis and destruction of
virus by macrophages
21. Cell-mediated immunity (CMI)
CMI prevents infection of target organs and promotes recovery from
disease by destroying virus and virus-infected cells. The different
mechanisms involved for virus destruction are as follows
1. Cytolysis by cytotoxic T-cells and Natural-killer (NK) cells
2. Antibody-dependent cell-mediated cytotoxicity (ADCC)
3. Antibody-complement-mediated cytotoxicity
22. Laboratory diagnosis of viral infections
Following are indications for laboratory diagnosis of viral infections
1. For proper management of certain diseases
2. Diagnosis of diseases caused by viruses for which antiviral
chemotherapy is available (herpes viruses)
3. Screening of blood donors for HIV and HBV
4. Early detection of epidemics like influenza, poliomyelitis,
encephalitis etc to initiate appropriate control measures
In the laboratory, the following methods are commonly employed
1. Direct demonstration of virus and its components
2. Isolation of virus
3. Detection of the specific antibodies
23. 1. Direct demonstration of virus and its components
a) Electron Microscopy
b) Immunoelectron microscopy
c) Fluorescent Microscopy
d) Light Microscopy
e) Viral antigens can be detected by ELISA,
RIA, latex agglutination
f) Nucleic acid probes
g) PCR
24. Detection of viruses in specimens by electron microscopy
Specimen
Viruses
Faeces
Rotavirus, hepatitis A virus,
adenovirus, Norwalk virus,
astrovirus
Vesicular fluid
Herpes simplex, Varicellazoster
CSF
Enterovirus, Varicella-zoster
Urine
Cytomegalovirus (CMV)
25. 2. Isolation of virus
This is the commonest method used in the diagnosis of virus
infections
The specimen should be collected properly and transported with
least delay to the laboratory
Most viruses are heat labile, therefore, refrigeration is essential
during transport
The methods used for isolation depend on the virus sought
Since, many viruses (eg: adenoviruses, enteroviruses) are
frequently found in normal individuals, therefore the results of
isolation should always be correlated with clinical data
26. 3. Detection of specific antibodies
The demonstration of a rise in titre of antiviral antibodies strongly
suggest the active infection
(Ist sample – early in the course of the disease and the convalescent
sample – 10-14 days later)
Examination of a single sample of serum is meaningful when IgM
specific antibodies are detected
The serological techniques employed would depend on the virus,
but those in general use are neutralisation, ELISA, haemagglutination
inhibition, complement fixation test, immunofluorescence and
latex agglutination tests
31. Live viral vaccines
They are prepared from
Attenuated strain (eg: yellow fever vaccines)
Temperature sensitive (ts) mutants (eg: influenza)
Live recombinant viruses (eg: influenza)
Advantages
1. A single dose of live vaccine is usually sufficient
2. They may be administered by the route of natural infection so that
local immunity is induced
32. 3. They induce a wide spectrum of immunoglobulins against the whole
range of viral antigens
4. They also induce cell mediated immunity
5. They can in general be prepared more economically, and
administered more convenientlly for mass immunisation
Disadvantages
1. There is a risk, however remote, of reversion of virulence
2. The vaccine may be contaminated with potentially dangerous viruses
(eg: oncogenic viruses)
3. Live viral vaccines are heat-labile and they have to be kept
under strict refrigeration
33. 4. Interference by preexisting viruses
5. The virus may spread from the vaccinees to contact
6. Some live viral vaccines may cause local but remote complications
Killed viral vaccines
Killed vaccines are prepared by inactivating viruses with heat, phenol,
beta-propiolactone and formaldehyde
Advantages
1. Safety and stability
2. They can be given in combination as polyvalent vaccines
3. There is no danger of spread of virus from the vaccinee
34. Disadvantages
1. Multiple injections are needed
2. These vaccines have to be given by injection, therefore,
local immunity (IgA immunoglobulins) immunity fails to develop
3. Cell mediated immunity is not induced
Passive immunisation
Passive immunisation with human gammaglobulin, convalescent
serum or specific immune globulin gives temporary protection against
many viral diseases (eg: measles, mumps and infectious hepatitis)
Indicated only when nonimmune individuals who are at special risk
are exposed to infection
Combined active and passive immunisation is an established method
for the prevention of rabies
35. Commonly used viral vaccines
Type of vaccine
Mode of preparation
Live viral vaccines
Measles
Attenuated virus grown in cell culture
Mumps
Attenuated virus grown in chick embryo fibroblast culture
Rubella
Attenuated virus grown in cell culture
Poliomyelitis (Sabin)
Avirulent strain grown in monkey kidney cell culture
Inflenza
a)Live (attenuated)
b) Live (mutant)
c) Live (recombinant)
a)Virus attenuated by serial passage in eggs
b)Use of ts mutant which are avirulent
c)Recombinants with surface antigens of new strains
and growth characters of established strains
Yellow fever (17D)
Attenuated virus grown in chick embryo
Killed viral vaccines
Hepatitis B
HBs Ag from human carrier sera
Rabies
Influenza (subunit)
Virus disintegrated with sodium deoxycholate
Poliomyelitis (Salk)
Virulent strain grown in monkey kidney cell culture
36. Chemoprophylaxis and chemotherapy of viral diseases
Mode of action
Antiviral agents
Inhibits viral DNA polymerase
a)
b)
c)
Inhibits reverse transcriptase
a)
b)
c)
Inhibits proteases
a)
b)
c)
d)
Acyclovir
Ganciclovir
Ribavirin
Active against
a)
b)
c)
Herpes simplex, VZV
Cytomegalovirus
RSV, Lassa virus
Zidovudine
Dideoxycytidine
Dideoxyinosine
HIV
Indinavir
Nelfinavir
Ritonavir
Saquinavir
HIV
Blocks penetration of virus
into cells
Amantadine
Influenza virus
Inhibits protein synthesis
Interferons
Many viruses
Table: Antiviral agents and their modes of action
