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Microbiology
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Virology

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Atul K Shankar

36

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ESSAY

Classify Rhabdovirus. Describe in detail about the pathogenesis, lab

diagnosis & prophylaxis of rabies.
Rhabdoviruses are bullet-shaped, enveloped viruses with a single-stranded RNA
genome. Rhabdovirus infect mammals, reptiles, birds, fish, insects and plants

CLASSIFICATION OF RHABDOVIRUS

Rhabdoviruses belong to 2 genera:

- Vesiculovirus
o Vesicular stomatitis virus
- Lyssavirus
o Rabies virus

PATHOGENICITY OF RABIES

Etiology

- Human infection is caused by the bite of rabid dogs/ other animals

- Virus, present in the saliva, enters the wound.
- If left untreated, rabies may develop.

Pathogenesis

- Virus appears to multiply in the muscles, connective tissue or nerves at the site
of deposition
- Penetrates the nerve endings and travels in the axoplasm towards the spinal
cord and brain
- Movement is passive
- The infection spreads centripetally from the axon to the neuronal bodies and
progressively up the spinal cord through the synapses & ascends rapidly to
the brain
- Multiplies and spreads centrifugally along the nerve trunks to various parts of
the body (including salivary glands)
o It multiplies in the salivary glands¸ and is shed in saliva
- Ultimately, the virus reaches every tissue in the body
o Can be interrupted at any stage by death
- Virus is almost invariably present in the cornea and facial skin of patients

Clinical Stages

- Prodrome
o Onset is marked by prodromal symptoms (fever, headache, malaise,
fatigue and anorexia)
o Early symptom is often a neuritic type of pain/paresthesia and
fasciculation at the site of virus entry.
 o Characterised by
 Apprehension, anxiety, agitation, irritability, nervousness,
insomnia and depression – usually lasts 2-4 days
- Acute Encephalitic Phase
o Usually begins with hyperactivity
 Characteristically intermittent
 Bouts of bizarre behaviour, agitation or seizures
 May be spontaneous or precipitated by external stimuli
o Pathognomonic feature is difficulty in drinking
 Attempts to drink bring on painful spasms of the pharynx and
larynx – producing choking or gagging
- Coma
- Death
o Usually occur within 1-6 days due to respiratory arrest during
convulsions.

LAB DIAGNOSIS OF RABIES

Specimen

- Corneal smears
- Skin biopsy
- Saliva (ante-mortem)
- Brain (post-mortem)

Direct microscopy

- Ante-mortem
o Demonstration of rabies virus antigens by Immunofluorescence
o Direct Immunofluorescence
 Done using monoclonal antibodies tagged with fluorescein
isothiocyanate
 Immunoperoxidase staining can be used in antigen in tissues
- Post-mortem
o Demonstration of Negri bodies in the brain
Culture Isolation

- Tissue culture
- Rapid and sensitive method
- Virus isolation is identified by Immunofluorescence
- Positive IF test can be obtained 2-4 days after inoculation
- Identity of the isolate can be established by the neutralisation test with
specific anti-rabies antibody

Antibody Demonstration

- High titre antibodies are present in the CSF in rabies but not after
immunisation.
- Demonstration can therefore be used for diagnosis
o ELISA is used
o Limited in antemortem diagnosis as the disease is largely fatal

Molecular Methods

- Detection of rabies virus RNA by reverse transcription PCR

PROPHYLAXIS OF RABIES

- Pre-exposure
o Specific prophylaxis is ideally given before exposure to infection.
- Post-exposure
o Consists of local treatment, active immunisation with anti-rabic
vaccines and passive immunisation with antirabies serum

Local Treatment

- Prompt cauterisation of the wound after viral deposition helps destroy the
virus
o Wound is washed well immediately with soap and water
o The wound is then treated with quaternary ammonium compounds,
tincture or aqueous solution of iodine, or alcohol
- In severe wounds
o Antirabic serum may be applied topically and infiltrated around the
wound.

Anti-rabic Vaccines

- 2 types; Neural & Non-neural

- Neural Vaccines
o Suspensions of nervous tissues of animals infected with the fixed rabies
virus
o Poor immunogens
o Encephalitogenic
o Examples include; Semple, Beta propriolacton, Suckling mouse brain
 - Non-neural vaccines
o 2 types; Egg Vaccines & Tissue culture vaccines
o Egg Vaccines
 Duck Egg Vaccine
 Live attenuated chick embryo vaccines
 Low Egg Passage Vaccine (LEP)
 High Egg Passage Vaccine (HEP)
o Tissue Culture Vaccines
 Human Diploid Cell Vaccine
o Subunit vaccine
 Glycoprotein subunit on the virus surface has been cloned and
recombinant vaccines have been produced.
 Still in the experimental stage

Passive Immunisation

- Equine Rabies Immune Globulin (ERIG)

o Manufactured by hyperimmunisation of horses
o Crude equine anti-rabies serum is not to be used as it is liable to induce
anaphylactic reactions
o Purified ERIG is much safer
- Human Rabies Immune Globulin (HRIG)
o Limited in availability
o More costly
o HRIG is preferred over ERIG
o Free from danger from the danger of sensitization
 Should also be free from HIV and Hepatitis viruses
 Classify Picornovirus. Describe the pathogenesis, lab diagnosis &
prophylaxis of Poliomyelitis
CLASSIFICATION OF PICORNOVIRUS

- Picornoviruses are classified into 4 genera due to their medical importance:

o Enterovirus – infects the intestinal tract
o Rhinovirus – infects the nasopharynx
o Hepatovirus
o Parechovirus

PATHOGENESIS OF POLIOMYELITIS

Transmission

- Virus enters by the oral route through ingestion of food and water
contaminated with human faeces.
- Colonises the nasopharynx and multiplies initially
- May be found in the throat or feces in initial phases.
- Passes down to Peyer’s patches and the epithelial cells of the alimentary
canal lymphatic tissues

Spread

- Spreads to the regional lymph nodes and enters the bloodstream

- After further multiplication in the reticuloendothelial system, virus enters the
bloodstream again and is carried to the spinal cord and brain
- Virus can pass along the axon of peripheral nerves to the central nervous
system
- Direct neural transmission to the central nervous system may also occur under
special circumstances
- In the CNS, virus multiplies selectively in the neurons and destroys them.
- Earliest change is degeneration of Nissl bodies (chromatolysis)
- Nuclear changes follow.
- When degeneration becomes irreversible, necrotic cell lyses or is
phagocytosed by leucocytes or macrophages
o Lesions are mostly found in the anterior horns of the spinal cord –
causes flaccid paralysis

CLINICAL FEATURES

- Inapparent infection
- Abortive poliomyelitis (minor illness)
o primary viremia consisting of fever, headache, sore throat and malaise
- Paralytic poliomyelitis (major illness)
o Fever returns with headache, stiff neck
o Marks the stage of viral invasion of CNS
- Non-paralytic poliomyelitis
LAB DIAGNOSIS OF POLIOMYELITIS

Specimen

- Throat swab
- Feces/rectal swabs
- Blood
- CSF

Viral Isolation

- Isolation of virus in tissue culture is the best method

- Virus can be isolated from blood during primary viremia
o 3-5 days after infection
o Before neutralising antibodies appear
- Virus can be isolated from the throat in the early stages of the disease
- Virus isolation from feces is usually possible in over 80% of patients in the 1st
week
o Best results are obtained by testing faecal samples collected on 2
separate days
- Poliovirus is rarely isolated from CSF
o Can be obtained from the spinal cord and brain

Serodiagnosis

- Antibody rise can be demonstrated in paired sera by

- neutralisation
- complement fixation
o useful to identify exposure to the poliovirus but not for type-specific
diagnosis

Molecular diagnosis

- Reverse transcriptase PCR

o PCR-based tests have been improved the demonstration of viral RNA in
CSF
- Sequencing
o 3 types of strains may be in a circulation
 Wild Virus
 Oral Polio Vaccine virus strain
 Vaccine derived polioviruses

PROPHYLAXIS OF POLIOMYELITIS

- Oral polio vaccine (OPV) – Sabin Type

- Intramuscular Polio Vaccine (IPV) – Salk type
Classify Herpes virus. Write in detail about morphology, pathogenesis &
lab diagnosis of Herpes Simplex Virus
CLASSIFICATION OF HUMAN HERPES VIRUS

Human Herpes Virus is classified into 8 types:

- Type 1 – Herpes Simplex Virus Type I

- Type 2 – Herpes Simplex Virus Type II
- Type 3 – Varicella Zoster Virus
- Type 4 – Epstein-Barr Virus
- Type 5 – Cytomegalovirus
- Type 6 – Human B Cell Lymphotropic Virus
- Type 7 – RK Virus
- Type 8 – Human Herpes Virus Type 8

Herpesviridae family is divided into 3 subfamilies based on biological, physical and

genetic properties:

- Alpha Herpes Virus

o Relatively short replicative cycle
o Tendency to cause latent infection in the sensory ganglia
o Examples are Herpes Simplex Viruses and Varicella Zoster virus
- Beta Herpes Virus
o Replicate slowly
o Grow best in fibroblasts
o Have tendency to cause enlargement of infected cells and latent
infection of the salivary gland and other organs.
o In culture, cytopathic effect is slow
o Virus remains cell associated
o Examples are Cytomegalovirus, Human B Cell Lymphotropic Virus, and
RK virus
- Gamma Herpes Virus
o have a narrow host range
o replicates in lymphoblastoid cells
o specific for either B or T lymphocytes
o frequently cause latent infection in lymphoid tissue
o Example is Epstein-Barr Virus

MORPHOLOGY OF HERPES SIMPLEX VIRUS

- Capsid is icosahedral enclosing the core containing the linear double-

stranded DNA genome
- Nucleocapsid is surrounded by lipid envelope derived from the modified host
cell nuclear membrane
- Between envelope and the capsid is amorphous structure called ‘tegument’.
PATHOGENESIS OF HERPES SIMPLEX VIRUS

- Primary Infection
o Usually acquired in early childhood
- Humans are the only natural hosts
- Sources of infection are saliva, skin lesions or respiratory secretions (3 S –
Saliva, Skin Lesions, Secretions)

Transmission:

- Transmission occurs by close contact

- May be venereal in genital herpes

Pathogenesis:

- Virus enters through defects in the skin, or mucous membranes

o Multiplies locally, with cell-to-cell spread
- Virus enters cutaneous nerve fibres and is transported intra-axonally to the
ganglia where it replicates.
- Centrifugal migration of the virus can take place from the ganglia to the skin
and mucosa to cause cutaneous and mucosal lesions
- Virus remains latent in the ganglia, particularly in the trigeminal and sacral
nerves
o These viruses are reactivated periodically in some individuals
 Causes recurrent oral and genital lesions
- Typical herpes lesions are:
o Thin-walled, umbilicated vesicles
o The roof of the vesicles break down, leaving tiny superficial ulcers
o They heal without scarring
o Primary infections are more severe and widespread, and associated
with systemic manifestations
o Recurrent infections are more localised
 HSV 1 produces above the waist
 HSV 2 produces below the waist

Clinical Features:

- Cutaneous Infections:
o Most common site is on the face
o Typical lesion is a fever blister (‘herpes febrilis’)
 Exposure to sun may bring on such reactivation
o Eczema herpeticum
 Generalised eruption caused by herpes infection in children
suffering from eczema
 Crops of vesicles appear on the affected area with widespread
ulceration
- Mucosal:
o Buccal mucosa is most affected
o Gingivostomatitis and pharyngitis are the most frequent conditions in
primary infection, and recurrent herpes labialis in recurrent infection
o Vesicles may ulcerate and become secondarily infected.
- Opthalmic
o HSV infection is the most common cause of corneal blindness in some
developed countries
o Acute keratohepatitis may occur by itself or by extension from facial
herpes
o Follicular conjunctivitis with vesicle formation on the lids is another
manifestation
- Nervous System:
o HSV encephalitis is the most common sporadic acute viral encephalitis
 Has an acute onset
 With fever and focal neurological symptoms
o HSV can cause sacral autonomic dysfunction and also rarely
transverse myelitis or the Guillian-Barre Syndrome.
o HSV has been implication in the causation of Bell’s Palsy
- Visceral:
o HSV oesophagitis may cause Dysphagia, substernal pain and weight
loss
o May involve the respiratory tract
 Causing tracheobronchitis, and pneumonitis
o HSV is an uncommon cause of hepatitis
o Erythema multiforme may be seen in association with HSV infection.
o Disseminated HSV infection may occur in patients with
immunodeficiency, malnutrition or burns
- Genital:
o In men, lesions mainly occur on the penis or in the urethra, causing
Urethritis
o In women, the cervix, vagina, vulva and perineum are affected.
o When only cervix is involved, the infection is usually more
asymptomatic
o The primary infection is usually more serious, accompanied by
systemic features like fever and malaise
o Followed by several recurrent episodes which are milder
o Vesiculo-ulcerative lesions may be very painful
o Rectal & perineal lesions occur in homosexuals
o Both types of HSV may cause genital lesions, though HSV2 is
responsible more frequently and causes many more recurrences
- Congenital
o Transplacental infection with HSV 1 or 2 can lead to congenital
malformations, but this is rare.
o Caesarian section may prevent infection.
LAB DIAGNOSIS OF HERPES SIMPLEX VIRUS

- Specimen:
o Vesicle fluid
o Skin Swabs
o Saliva
o Corneal Scrapings
o CSF
o Brain biopsy

- Microscopy:
o Tzanck Smear is a rapid, fairly sensitive and inexpensive diagnostic
method
 Smears are prepared and stained with 1% aqueous solution of
Toluidine blue 0 for 15 seconds
 Demonstrates multinucleated giant cells with faceted nuclei
and homogeneously stained ‘ground glass’ chromatin, or
‘TZANCK CELLS’
 Intranuclear type A Inclusion Bodies may be seen in Giemsa
stained smears
o Virus particle may also be demonstrated under the electron
microscope
 It is not possible to differentiate between herpes simplex and
Varicella zoster by microscopy.
o Herpes virus antigen may be demonstrated in smears or sections from
lesions by the fluorescent antibody technique
 Provides reliable and speedy diagnosis in encephalitis

- Serology:
o Rise in antibodies titre may be demonstrated by ELISA, neutralisation or
complement fixation tests
o In recurrent or re-infection herpes, there may be little change in the
antibody titre

- Polymerase Chain Reaction:

o PCR based detection methods are used more often for diagnosis

- Virus Isolation:
o Tissue culture for virus isolation
o Typical cytopathic changes may appear as early as 24-28 hours
o Cultures should be observed for 2 weeks before being declared
negative
o Drug susceptibility can be test in cell cultures
 Classify Human Herpes Virus. Describe the pathogenesis and lab
diagnosis of Varicella-Zoster Virus
CLASSIFICATION OF HUMAN HERPES VIRUS

Human Herpes Virus is classified into 8 types:

- Type 1 – Herpes Simplex Virus Type I

- Type 2 – Herpes Simplex Virus Type II
- Type 3 – Varicella Zoster Virus
- Type 4 – Epstein-Barr Virus
- Type 5 – Cytomegalovirus
- Type 6 – Human B Cell Lymphotropic Virus
- Type 7 – RK Virus
- Type 8 – Human Herpes Virus Type 8

Herpesviridae family is divided into 3 subfamilies based on biological, physical and

genetic properties:

- Alpha Herpes Virus

o Relatively short replicative cycle
o Tendency to cause latent infection in the sensory ganglia
o Examples are Herpes Simplex Viruses and Varicella Zoster virus

- Beta Herpes Virus

o Replicate slowly
o Grow best in fibroblasts
o Have tendency to cause enlargement of infected cells and latent
infection of the salivary gland and other organs.
o In culture, cytopathic effect is slow
o Virus remains cell associated
o Examples are Cytomegalovirus, Human B Cell Lymphotropic Virus, and
RK virus

- Gamma Herpes Virus

o have a narrow host range
o replicates in lymphoblastoid cells
o specific for either B or T lymphocytes
o frequently cause latent infection in lymphoid tissue
o Example is Epstein-Barr Virus
Varicella-Zoster Virus:

Varicella Zoster Virus is the causative agent for Varicella, or ‘Chicken Pox’, and
Herpes Zoster, or ‘Shingles’.

Morphology:

- Capsid is icosahedral enclosing the core containing the linear double-

stranded DNA genome
- Nucleocapsid is surrounded by lipid envelope derived from the modified host
cell nuclear membrane
- Between envelope and the capsid is amorphous structure called ‘tegument’.

Pathogenesis of Varicella:

- Portal of entry is the respiratory tract or conjunctiva

- After an incubation period of 2 weeks, the lesions begin to appear.
- The patient is considered to be infectious during 2 days before and 5 days
after the onset of lesions.
- Evolution of the rash is so rapid that the various stages cannot be readily
followed
o Rash is centripetal in distribution
o Affecting mainly the trunk and sparing the distal parts of the limbs
o Very superficial without involving the deeper layers of the skin
 Resembles a dew-drop lying on the skin
o The rash appears in crops during the first 3-4 days of the disease
o It matures very quickly, beginning to crust within 48 hours.

Lab Diagnosis of Varicella:

- Microscopy:
o Multinucleated giant cells and type A intranuclear inclusion bodies are
seen in smears prepared by Tzanck Smears, and stained with toluidine
blue, Giemsa or Papanicolou stain.
o Electron microscopy of vesicle fluid may demonstrate the virus with
typical herpes morphology
- Virus Isolation:
o May be attempted from the buccal or cutaneous lesions in the early
stages by inoculating human amnion, human fibroblast, HeLa or Vero
cells
- Serology:
o Virus antigen can be detected by:
 Immunofluorescence in skin scrapings
 Counter-immunoelectrophoresis with zoster immune serum in
vesicle fluid
 Enzyme Linked Immunosorbent Assay (ELISA)
 Polymerase Chain Reaction (PCR)
Pathogenesis of Herpes Zoster:

- Rash is typically unilateral and confined to the area supplied by a single

sensory ganglion
- The most common site are the areas innervated by spinal cord segments T3 to
L2, and the ophthalmic branch of the trigeminal nerve
- Lesions are identical in nature to the Varicella lesions, except for their limited
distribution
- Rash heals in about 2 weeks
- Pain and paraesthesia at the affected area may persist for weeks or months
- Other complications include:
1) Lower Motor Neuron Paralysis
2) Meningoencephalitis
3) Generalised Zoster – where lesions are scattered widely, due to
haematogenous dissemination of the virus
- Herpes Zoster Ophthalmicus is a common and troublesome presentation
- Ramsay Hunt Syndrome:
o Rare form of zoster affecting the facial nerve
o There is eruption on the tympanic membrane and the external auditory
canal
o There is often facial palsy
o Chronic or recurrent zoster is often seen in HIV infected patients

Laboratory Diagnosis of Herpes Zoster:

- Diagnosis is made clinically

- Laboratory diagnosis and treatment are the same as that of Varicella
- Microscopy:
o Multinucleated giant cells and type A intranuclear inclusion bodies are
seen in smears prepared by Tzanck Smears, and stained with toluidine
blue, Giemsa or Papanicolou stain.
o Electron microscopy of vesicle fluid may demonstrate the virus with
typical herpes morphology

- Virus Isolation:
o May be attempted from the buccal or cutaneous lesions in the early
stages by inoculating human amnion, human fibroblast, HeLa or Vero
cells
o
- Serology:
o Virus antigen can be detected by:
 Immunofluorescence in skin scrapings
 Counter-immunoelectrophoresis with zoster immune serum in
vesicle fluid
 Enzyme Linked Immunosorbent Assay (ELISA)
 Polymerase Chain Reaction (PCR)
 List the Arboviruses prevalent in India. Describe the etiology,
pathogenesis & lab diagnosis of Japanese B Encephalitis
The Arboviruses prevalent in India are:

- Alphavirus
- Flavivirus
- Bunyavirus
- Phlebovirus
- Nairovirus
- Hantavirus
- Orbivirus
- Arenavirus
- Marburgvirus

Japanese B Encephalitis:

Pathogenesis:

- The causative organism for Japanese B Encephalitis is flavivirus

- May be associated with more than 1 syndrome
- Virus enters the body via mosquito bite
- After multiplication in the reticuloendothelial system, viremia of varying
duration ensues and the virus is transported to the brain
- Infection occurs with varying degrees of severity.

Clinical Features:

- Japanese encephalitis virus causes the most serious clinical disease.

- Disease has an abrupt onset fever, headache and vomiting
- After 1-6 days, signs of encephalitis set in with:
o Nuchal rigidity
o Convulsions
o Altered sensorium
o Coma
- Fever is high and continuous
- There is a presence of neutrophil leucocytosis in peripheral blood and
pleocytosis with normal or raised sugar levels and slightly elevated protein
levels in the CSF
- Convalescence may take several weeks
- Infection in pregnant women during 1st and 2nd trimester has led to fetal death.
- Large majority of infections are asymptomatic
Lab Diagnosis:

- Specimen:
o Since all arboviruses are viremic, blood should be collected.
o Other samples are CSF

- Virus Isolation:
o Specimens are inoculated intracerebrally into suckling mice
o Animals develop fatal encephatlitis
o Flavivirus can also be isolated in cell cultures namely, HeLa, BHK, MRC-
5 and Vero.
o Mosquito cell lines have been used for isolation
o Isolates are identified by:
 Haemagglutination inhibition
 Complement fixation
 Immunofluorescence
 Immunochromatography
 ELISA
 Neutralisation

- Serology:
o Diagnosis can be made by demonstrating IgM antibodies in acute
phase by ELISA or rise in IgG titres in paired serum samples by
haemagglutination inhibition, complement fixation test or neutralisation
tests.
o These tests are time-consuming and laborious
o Often complicated due to antigenic cross-reaction between related
viruses
o Detection of viral proteins & antigens, or RNA by molecular methods
are more specific and rapid
o They have replaced conventional CFT, HAI and neutralisation tests.
What are Retroviruses? Describe the morphology & pathogenesis of HIV.
Describe the lab diagnosis of AIDS.
Retroviruses are enveloped, spherical viruses that are released by budding through
the host cell membrane. They are approximately 100nm in size. The genome consists
of 2 identical, linear, single-stranded RNA molecules. The characteristic feature is the
presence of RNA dependent DNA polymerase, or ‘Reverse Transcriptase’. Reverse
Transcriptase prepares a DNA copy of the retroviral RNA genome, forming an RNA-
DNA hybrid, and then its double-stranded DNA form, called provirus, which is
incorporated into the DNA of the infected host cell.

Morphology of HIV:

- Envelope:
o HIV is a spherical, enveloped virus
o Nucleocapsid has an outer icosahedral shell and an inner cone-
shaped core, enclosing the ribonucleoproteins.
- Genome:
o The genome is composed of 2 identical single-stranded, positive-sense
RNA copies, with reverse transcriptase enzyme
- Lipoprotein Envelope:
o When the naked virus buds out through the host cell surface during
viral replication, it acquires a lipoprotein envelope, which consists of
lipid derived from the host cell membrane and glycoproteins coded
by the virus.
o The major virus-coded envelope proteins are the projecting knob-like
spikes on the surface and the anchoring transmembrane pedicles.
o Spikes constitute the main surface component of the virus
 Bind to the CD4 receptors on susceptible host cells
o Transmembrane pedicles cause cell fusion.

Pathogenesis of HIV:

- Infection is acquired when the virus enters the blood or tissues of a person
and comes into contact with a suitable host cell, principally the CD4
lymphocyte.
- Cell Receptor for Virus Attachment:
o Receptor for the virus is any cell bearing the CD4 antigen
o Follicular dendritic cells from tonsils can be infected by HIV without the
involvement of CD4.
o Specific binding of the virus to the CD4 receptor is by the envelope
glycoprotein ‘gp120’.
o Cell fusion is essential for infection to take place
o Brought about by transmembrane gp41
o Binding to the CD4 receptor requires the participation of a co-receptor
molecule, which has been identified as CXCR-4 for T cell-tropic HIV
strains and CCR-5 for macrophage-tropic strains.
 - Replication:
o After fusion of the virus with the host cell membrane, HIV genome is
uncoated and internalised into the host cell.
o Viral reverse transcriptase mediates the transcription of its RNA into
double-stranded DNA
 dsDNA is integrated into the genome of the infected cell
through the action of viral enzyme integrase, causing a latent
infection
- Primary Pathogenic Mechanism:
o Damage to the CD4+T lymphocytes
o Infection of T lymphocytes prevents secretion of normal amounts of
interleukin-2, gamma-interferon, and other lymphokines.
o This suppresses cell-mediated immune response
- There is also polyclonal activation of B lymphocytes leading to
hypergammaglobulinaemia of all classes of immunoglobulins (IgG and IgA in
particular)
- Monocyte-macrophage function is affected due to lack of secretion of
activating factors by T4 lymphocyes
o As a result, chemotaxis, antigen presentation and intracellular killing by
monocytes and macrophages are diminished.

Lab Diagnosis of AIDS:

- Viral Isolation
o Done in containment laboratories
o HIV is isolated from infected persons from the peripheral lymphocytes
by co-cultivation
o Viral replication can be detected by the demonstration of reverse
transcriptase activity as well as antigens, in the culture supernatant.
- Detection of Antibodies
o DNA Polymerase Chain Reaction
 Proviral DNA is amplified and detected by probes based on
nucleic acid hybridisation
 Highly sensitive and specific
o RT-PCR
 Uses an enzymatic method to amplify HIV RNA
 Detects the progression of diseases and monitor therapy
response
o bDNA assay
 sequential oligonucleotide hybridisation steps are used to
amplify the viral DNA
- Detection of Antigens:
o ELISA
o Western Blot
o Line Immunoassays (LIAs)
Classify Hepatitis Viruses. Detail the pathogenesis, clinical features, lab
diagnosis and prophylaxis of Hepatitis B
Classification of Hepatitis Viruses:

- 6 types:
o Hepatitis A
 Also known as ‘infectious hepatitis’
 Transmitted by faecal-oral route
o Hepatitis B
 Also known as ‘serum hepatitis’
 Transmitted by inoculation or blood transfusions
o Hepatitis C
 Later identified as causing many non A non B transfusion
associated Hepatitis
o Hepatitis D
 Defective virus
 Dependent on the helper functions of type B virus
o Hepatitis E
 Another type of non-A non-B hepatitis
 Transmitted by faecal-oral route
 Prevalent in developing countries
o Hepatitis G
 Can also cause hepatitis
 Not yet adequately understood

Clinical Features of Hepatitis B:

- Incubation period is long

- Clinical picture is similar to that of Type A, tends to be more severe and
protracted.
- Onset is insidious and fever is not prominent
- Extra hepatic complications like arthralgia, urticaria and rarely polyarteritis or
glomerulonephritis may occur.
o Ascribed to circulating immune complexes containing the viral surface
antigen

Lab Diagnosis:

- Detection of viral markers

- These viral markers are:
o HBsAg
o HBcAg
o HBeAg
 - HBsAg:
o First marker to appear in blood after infection
o Detectable even before elevation of transaminases and onset of
clinical illness
o Remains in circulation throughout the icteric or symptomatic course of
the disease.
o In a typical case, it disappears within about 2 months of the start of
clinical disease
 It may sometimes last for 6 months and even beyond
o When it is no longer detectable, anti-HBs appear and remains for very
long periods
- HBcAg
o Not demonstrable in circulation
 it is enclosed within the HBsAg coat
 its antibody appears in the serum for a week or 2 after its
appearance
o it is therefore the earliest antibody marker to be seen in blood, long
before anti-HBe or anti-HBs
o it serves as a useful indicator of prior infection with HBV
o Initially, anti-HBc is predominantly IgM, but after 6 months, it is mainly
IgG.
- HBeAg
o Appears in blood concurrently with HBsAg
o Circulating HBeAg is an indication of active intra-hepatic viral
replication, and the presence in blood of DNA Polymerase, HBV DNA
and virions, reflecting high infectivity.
o Disappearance of HBeAg coincides with the fall of transaminase levels
in blood
o Followed by the appearance of anti-HBe

Prophylaxis of Hepatitis B:

Immunisation:

o Passive Immunisation:
 Hyperimmune Hepatitis B Immune Globulin (HBIG)
 Does not prevent infection, but protects against illness and the
carriers state
o Active Immunisation:
 Vaccine containing all antigenic components of HBsAg
 Booster dose are given to those at high risk
o Combined Immunisation
 Used for non-immune persons exposed to HBV
 When HBIG is unavailable, the vaccine given alone has been
reported to provide protection
SHORT NOTES

Hepatitis C
- Virus with a liner, single-stranded RNA genome, enclosed within a core and
surrounded by an envelope, carrying glycoprotein spikes
- Resembles flaviviruses in structure and organisation

Clinical Features:

- Incubation period is long (15-160 days)

- Acute illness is mild or aniecteric
- Overt jaundice is seen in 5% of patients
- 50-80% of cases progress to chronic hepatitis, with some developing cirrhosis
and hepatocellular carcinoma

Lab Diagnosis:

- Standard method of diagnosis is antibody detection by ELISA

- Confirmation by immunoblot assay is recommended
- In HCV infection, antibodies appear irregularly and late, limiting their
diagnostic utility.
- Culture is not yet established

Prophylaxis:

- Only general prophylaxis is possible (e.g. Blood Screening)

- No specific active or passive immunising agent is available.

Treatment:

- Prolonged treatment with Interferon Alpha

o Either alone or in combination with anti viral agents (ribavirin)

Viral Vaccines
- Viral Vaccines are of 3 types:
1) Live Vaccines:
o Initiate infection without causing any injury or disease
o Lasts several years but booster doses may be necessary
o Live vaccines are administered orally or parenterally
 Orally – Sabin Vaccine (OPV)
 Parenterally – Measles Vaccine
2) Killed Vaccines:
o Less immunogenic
o May be given orally or parenterally (more effective)
o Example: Salk vaccine (IPV)
3) Subunit Vaccines:
o Hepatitis B Vaccine
 Life Cycle of Bacteriophage
- Phages exhibits 2 different types of life cycles
o Lytic Cycle – intracellular multiplication culminates in lysis of host
bacterium and release of progeny virions
o Lysogenic Cycle – phage DNA becomes integrated with the bacterial
genome, replicating synchronously with it, causing no harm to the host
cells

Lytic Cycle:

- Adsorption
o Phage particles come into contact with bacterial cells by random
collision and attaches to the surface by its tail.
- Penetration
o Phage DNA is injected into the bacterial body through the hollow core.
o may be facilitated by the presence on the phage tail of lysozyme,
producing a hole on the bacterial wall for the entry of the phage
- Synthesis
o Synthesis of the phage components is initiated.
o First products are enzymes necessary for building of the complex
molecules, and later proteins appear
- Maturation
o DNA is condensed into a compact polyhedron and ‘packaged’ into
the head.
o Tail structures are added
- Release
o During replication of the phage, bacterial cell walls weaken and
assume a spherical shape
o Phage enzymes act on the weakened cell wall causing it to burst and
lyse, resulting in the release of mature daughter phages.

Lysogenic Cycle:

- Temperate phages enter into a symbiotic relationship with their host cells
without destroying them
- Following entry into the host cell, temperate phage nucleic acid becomes
integrated with the bacterial chromosome.
- The integrated phage nucleic acid is known as the prophage.
o Behaves like a segment of the host chromosome and replicates
synchronously with it – LYSOGENY
- Prophage confers certain new properties on the lysogenic bacterium
o Due to the synthesis of new proteins coded for by prophage DNA
- During multiplication of lysogenic bacteria, the prophage may become
excised from occasional cells.
- Excised prophage initiates lytic replication and the daughter phage particles
are released, and infect other bacterial cells, rendering them ‘lysogenic’
 Cultivation of Viruses
Animal Inoculation:

- Growth of the virus in inoculated animals may be indicated by death, disease

or visible lesions.
- Serial blind passages sometimes be necessary before evidence of virus
growth can be obtained.
- Disadvantages are:
o Immunity may interfere with viral growth
o animals often harbour latent viruses.
- Also used for the study of pathogenesis, immune response, epidemiology and
Oncogenesis
- Animals used for inoculation are mice, guinea pigs, rabbits and ferrets

Embryonated Eggs:

- Inoculation on the Chorioallantoic Membrane produces visible lesions

(pocks)
o Different viruses have different lesion morphology.
o Each infectious virus particle can form one pock
o Pock counting is used for assay of pock-forming viruses such as Variola
or Vaccinia
- Inoculation into the allantoic cavity provides a rich yield of influenza and
some paramyxoviruses.
o Employed for growing influenza virus for vaccine production.
- Inoculation into the amniotic sac is employed for the primary isolation of the
influenza virus
- Yolk sac inoculation is used for cultivation of some viruses, Chlamydia and
rickettsiae

Tissue Cultures:

- Types:
o Organ Culture
 E.g. tracheal ring organ culture is employed for the isolation of
coronavirus
o Explant Culture
 E.g. adenoid tissue explants cultures were used for isolation of
adenoviruses
o Cell Culture
 Primary Cultures – useful for isolation of viruses and their
cultivation for vaccine production
 Secondary Cell Strains – useful in isolation of some fastidious
pathogens and production of vaccines
 Continuous Cell Lines – used for vaccine manufacture (e.g.
Vero cell vaccine for rabies)
 Dengue Fever
- An acute febrile illness with 2 or more of the following manifestations:
o Headache
o Retro-orbital pain
o Myalgia
o Arthralgia
o Rash
o Haemorrhagic manifestations
- Causative agent is the Dengue virus
- Virus exists in 4 forms:
o DEN – 1
o DEN – 2
o DEN – 3
o DEN – 4
- Clinical Findings:
o Febrile Phase
 Patients develop a high grade fever of sudden onset
 Associated with headache, retrobulbar pain, photophobia
 Accompanied by facial flushing, skin erythema and pain in
back and limbs, lymphadenopathy and Maculopapular rash
 Fever is biphasic
o Critical Phase
 Patients become worse around the time of defervescence
 Temperature drops to 37.5-38 degrees and remains at this level.
 Progressive leukopenia followed by a rapid decrease in platelet
count usually precedes plasma leakage
- Lab Diagnosis:
o Virus can be isolated in the 1st week of illness
o Mainstay of diagnosis is detection of a non-structural viral protein
antigen
o Can be detected in the blood up to 7-10 days
o Demonstration of circulating IgM antibody
 Provides early diagnosis as it appears within 2-5 days of onset of
illness
 Persists for 1-3 months
 IgM ELISA test offers reliable diagnosis
o Strip Immunochromatographic Test for IgM
- Treatment:
o There is no specific treatment for dengue
o Supportive management,
 cold tepid sponging,
 paracetamol for fever
 fluid and electrolyte replacement
 platelet infusion
 Antigenic Drift & Shift
Antigenic Drift:

- gradual sequential change in antigenic structure, occurring regularly at

frequent intervals
- New antigens are still related to them
o Therefore they react with antisera to the predecessor virus strains to
varying degrees.
- Due to mutation and selection
o Process being influenced by the presence of antibodies to the
predecessor strains in the host population
- Accounts for the periodic epidemics of influenza

Antigenic Shift:

- Abrupt, drastic discontinuous variation in the antigenic structure

o Results in a novel virus strain unrelated antigenically to the predecessor
strains
o Such strains involve:
 Haemagglutinin
 Neuraminidase
 Or both
- Antibodies to predecessor viruses DO NOT neutralise the new variants
o it can therefore spread widely in the population, causing major
epidemics or pandemics
- Changes involved in antigenic shift are too extensive to be accounted for by
mutation.

MMR Vaccine (Mumps, Measles & Rubella Vaccine)

- Live attenuated vaccine composed of the RA 27/3 strain in combination with
measles and mumps components
- Vaccine is well tolerated, though minor reactions like lymphadenopathy, rash,
and arthralgia may sometimes occur
- It should not be given to immunodeficient subjects
- Pregnancy is an absolute contraindication and should be avoided for 3
months after vaccination
- Inadvertant administration of the vaccine to pregnant women may not
therefore lead to congenital defects in the baby, because it is not
teratogenic.
 Slow Virus Disease
- Group of infections in animals and human beings
- Characterised by a very long incubation period and a slow but relentless
course, terminating fatally.

Classification:

- Group A
o Slowly progressive infections of sheep
o Caused by serologically related, non-oncogenic retroviruses called
LENTIVIRUSES
- Group B
o Comprising of prion diseases of CNS:
 Scrapie
 Mink Encephalopathy
 Kuru & Creutzfeldt-Jakob Disease
 Collectively known as SUBACUTE SPONGIFORM VIRAL
ENCEPHALOPATHIES
- Group C
o Consists of 2 unrelated CNS diseases
 Subacute Sclerosing Panencephalitis
 Progressive Multifocal Leucoencephalopathy

Rotavirus
- 2 forms; Double Shelled Virus, or Single-Shelled Virus
- Classification:
o Rotavirus is divided into antigenic groups (A to G)
o Group A is divided into:
 Subgroup I and II by ELISA, CF or IAA
 Many serotypes (1,2,3 etc) by neutralisation tests
o Rotavirus strains can be classified into several electrophoretypes,
based on the patterns of migrations of the viral RNA
- Serological Techniques:
o IgM and IgG antibodies are demonstrated in the blood of infected
children
o Rotavirus share a common group antigen situated in the inner capsid
layer
- Treatment:
o Rotaviruses vaccines are in use
o Most common is RotaTeq (RV5) vaccine
o India has introduced an indigenously developed rotavirus vaccine
called Rotatrix (RV1)
o Both vaccines are administered orally
 Viral Diarrhoea
- Viral diarrhoea is caused by:
1) Norwalk Virus:
o Was shown to be responsible for an epidemic of gastroenteritis
affecting school children and teachers in Norwalk
o Can be demonstrated in feces by electron microscopy
o Antibody to the virus is detected by Immune electron microscopy and
radioimmunoassay
2) Rotavirus:
o Reported to cause outbreaks of diarrhoea in older children and adults
from China
o Called ‘Adult Diarrhoea Rotavirus’, or ‘ADRV’ – belongs to Group B
Rotaviruses
3) Adenovirus
o Several outbreaks of diarrhoea in children is associated with presence
of large numbers of adenoviruses in feces.
o Can be grown only with difficulty in tissue cultures
o Adenovirus-associated diarrhoea has been seen more often in the
summer months
4) Astrovirus
o Star-shaped particles
o Associated with some epidemics of diarrhoea in children
o Similar viruses have also been identified in lamb and calf diarrhoea
5) Coronavirus
o Well-established causes of acute diarrhoea in calves, piglets and dogs
o They have been observed in human feces, but their relation to
diarrhoea is uncertain.

Interferon
- Family of host coded proteins produced by cells on induction by viral or non-
viral inducers
- Has no direct action on viruses, but acts on other cells of the same species,
rendering them refractory to viral infection
- On exposure, cells produce a protein which selectively inhibits translation of
viral RNA, without affecting cellular mRNA.
- Interferons are species specific – antiviral effect on human cells by human IFN
- TYPES:
o Alpha interferon (IFN-alpha)
 Produced by leucocytes following induction by suitable viruses
o Beta Interferon (IFN-beta)
 Produced by fibroblasts and epithelial cells following stimulation
by viruses or polynucleotides
o Gamma Interferon (IFN-gamma)
 Produced by T lymphocytes, concerned with
immunomodulatory and anti-proliferative functions
 Chikungunya
- Alphavirus
- Transmitted by mosquito bite, specifically Aedes aegypgti

- 3 major genotypes:
o West African
o East/Central/South African ECSA
o Asian

- Reasons for Re-emergence

o Disease appears in epidemics after a gap of 10-20 years
o Reason for this is unknown

- Symptoms:
o Sudden onset of
 Fever
 Crippling joint pain
 Lymphadenopathy
 Conjunctivitis
o Maculopapular rash is common, although haemorrhagic
manifestations are rare.
o Fever is typically biphasic with a period of remission after 1-6 days

- Clinically, Chikungunya cannot be differentiated from uncomplicated

dengue
- Lab tests based on IgM detection can help in confirming.

- Diagnosis:
o Detection of IgM or IgG in a paired serum sample by ELISA
o Reverse transcriptase PCR can be used to detect viral RNA

- Treatment:
o There is no vaccine available.

Swine Flu
- A new H1N1 virus
- Detected in March 2009
- Reassortant between previously circulating swine flu and was also called
Swine origin influenza (S-OIV)
- Spreads from person to person
- Caused a pandemic
 Infectious Mononucleosis (Glandular Fever)
- Acute self-limited illness, usually seen in non-immune young adults following
primary infection with the Epstein-Barr Virus
- Characterised by:
o Fever
o Sore Throat
o Lymphadenopathy
o Presence of abnormal lymphocyte in peripheral blood smears
- Patients treated with Ampicillin may develop a maculopapular rash, due to
immune complex reaction to the drug
- Often there is associated hepatitis

Lab Diagnosis:

- Blood Examination:
o May show leukopenia in the initial phase due to a drop in the number
of polymorphs
o Later there is prominent leucocytosis, with the appearance of
abnormal mononuclear cells, characterised by:
 Deeply basophilic vacuolated cytoplasm
 Kidney shaped nuclei, showing a lattice of fenestrated
chromatin
 These atypical mononuclear cells are not virus-infected B
lymphocytes but lymphoblasts derived from T cells reactive to
the virus infection.
o Blood picture may sometimes resemble lymphocytic leukaemia
- Serology
o Paul-Bunnell Test:
 Standard diagnostic procedure
 Heterophile antibodies agglutinate sheep erythrocytes
 such antibodies may also occur after injections of sera and
sometimes even in normal individuals,
 Infectious mononucleosis antibodies may be differentiated by
absorption tests.
o Differential Agglutination Test:
 Differential absorption of agglutinins with red blood cells are
necessary
 Forssman antibody induced by injection of horse serum is
removed by treatment with guinea pig kidney and ox red cells
o Immunofluorescence and ELISA are commonly employed
o IgM antibody to VCA (Viral Capsid Antigen) appears soon after
primary infection and disappears in 1-2 weeks
 Reliable indication of primary infection
o Presence of Antibody to the EB nuclear antigen (EBNA) is also a useful
marker for primary infection.
 Cytomegalovirus
- Group of ubiquitous herpesvirus of humans and animals
- Characterised by:
o Enlargement of infected cells
o Prominent intranuclear inclusions
- Lead to prolonged latency in infected hosts.
- Causes severe disseminated disease
- Human CMV is unrelated antigenically to other herpesviruses, and even to
CMV of other speices

Clinical Features:

- Congenital Infections
o Intrauterine infection leads to fetal death or cytomegalic inclusion
disease of the newborn which is often fatal
o Generalised infection associated with Hepatosplenomegaly, jaundice,
thrombocytopenic purpura, and hemolytic anemia
o Other manifestations are:
 Chorioretinitis
 Cerebral calcification resembling congenital toxoplasmosis
- Infection in Infants
o Cytomegalic inclusion disease is almost exclusively found in infants
born to mothers, who develop primary CMV infection, during
pregnancy
o Perinatal infection may be acquired from the infected mother through
genital secretions or breast milk
- Infection in Children
o Primary infections in older children and adults are asymptomatic
o Heterophile, antibody-negative, infectious mononucleosis may be
seen
o More common following transfusion of CMV-infected blood (post-
transfusion mononucleosis)

Lab Diagnosis:

- Specimens
o Urine, saliva, semen and cervical secretions
- Isolation
o Growth in cultures can be detected early by using shell vial culture
o staining the cells with fluorescent tagged antibody to early antigens of
CMV
o demonstration of cytomegalic cells in centrifuged deposits from urine
or saliva in which inclusion bodies are seen – Owl’s Eye
- Serology
o CF, IHA, IF and ELISA are used to demonstrate presence of antibodies.
o Antigen detection is necessary for screening blood or organ donors
 Opportunistic Fungal Infections in HIV
The opportunistic fungal infections in HIV patients are:

1) Pneumocystis jirovecii (carinii)

2) Candidosis
3) Cryptococcosis
4) Aspergillosis
5) Histoplasmosis

Lab Diagnosis of Influenza

- Demonstration of the Virus Antigen:
o Demonstration of the virus antigen on the surface of the
nasopharyngeal cells by Immunofluorescence
- Isolation of the virus
o Readily obtained readily during the first two or three days of the illness
o Throat garglings are collected using broth saline or other suitable
buffered salt solution
o Specimen should should be treated with antibiotics to destroy bacteria
o Isolation may be made in eggs or in monkey kidney cell culture
o SUBTYPE IDENTIFICATION
 Made by haemagglutination inhibition test
 Inoculation into monkey kidney is the preferred method where
the facility is available
o Rapid results are obtained by demonstration of virus antigen by
Immunofluorescence
- Serology
o Haemagglutination Inhibition
 Convenient and sensitive test for serological diagnosis of
influenza
 Sera are diluted serially in haemagglutination plates and the
influenza virus suspension containing 4HA units added to each
cups
 Fowl Red Cells are then added.
o Complement Fixation Tests
 Done using V antigens for the demonstration of strain-specific
antibodies
 Due to complexity, CF tests are now used only rarely
o Radial Immunodiffusion Tests
 These tests in agarose gel have been described for the
identification of antibodies to the RNP antigen, Haemagglutinin
and neuraminidase
 More useful for screening
o Polymerase Chain Reaction
 Specific primers to the subtypes are used in a multiplex PCR
assay to identify the virus in a clinical specimen
 Viral Haemorrhagic Fevers
- Applies to a group of diseases
o Apparently zoonotic in nature, with features of haemorrhage caused
by viruses belonging to two families:
 Arenavirus
 Filovirus
o Usually cause asymptomatic infection in the local population but at
times they erupt in sudden outbreaks, killing large populations and
causing panic
- ARENAVIRUS:
o Assumed considerable medical importance
 Due to recognition that some members cause hemorrhagic
fevers in humans
 E.g. Argentinian and Bolivian hemorrhagic fevers and Lassa
Fever
o Lymphocytic Choriomeningitis
 Natural parasite of mice
 Most infections are asymptomatic but some may develop
influenza like illness
 LCM has been reported to account for 5-10% of sporadic viral
meningitis in human beings

o South American Haemorrhagic Fevers:

 Two related viruses; Junin & Machupo viruses
 Causes the Argentinian & Bolivian Haemorrhagic Fevers
respectively

o Lassa Fever
 Most highly publicised of viral haemorrhagic fevers
- FILOVIRUS:
o Ebola Virus:
 There were several cases of a similar hemorrhagic fever
occurred in the equatorial provinces of Sudan and Zaire
 Causative agent is morphologically identical to Marburg virus,
but antigenically distinct

o Marburg Virus
 Haemorrhagic fever that occurred simultaneously in lab workers
in Marburg, Frankfurt, and Belgrade in 1967
 Arose from tissues of African Green Monkeys to which the lab
worker were exposed
 Virus appears to persist in the body and has been isolated after
80 days of onset of illness from semen and anterior chamber of
the eye
 Oncogenic Viruses
RNA VIRUSES:

- Retroviruses
o Avian leukosis viruses
o Murine leukosis viruses
o Murine mammary tumour virus
o Leukosis-sarcoma virus of various animals
o Human T cell leukaemia viruses

DNA VIRUSES:

- Papovavirus:
o Papillomaviruses
o Polyomavirus
o Simian virus 40
o BK and JC viruses
- Poxvirus
o Molluscum contagiosum
o Yaba Virus
o Shope fibrome
- Adenovirus
- Herpes Virus
o Marek’s disease virus
o Lucke’s frog tumour virus
o Herpes virus - pan, papio, ateles and saimiri
o Epstein-Barr Virus
o Herpes Simplex Virus Types 1 and 2
o Cytomegalovirus
- Hepatitis Viruses
o Hepatitis B Virus
o Hepatitis C Virus

Antigens of Influenza Virus

- Internal Antigen:
o Ribonucleoprotein and hence called RNP antigen
o Found free in infected tissues and occurs in the supernatant
 Also called ‘Soluble’( S) Antigen
o M protein antigen:
 Type specific and distinct for A, B and C types of Influenza
viruses
- Surface Antigens
o Haemagglutinin – enables the virus to adsorb to mucoproteins
receptors on RBCS as well as respiratory epithelial cells
 Strain specific antigen and is capable of great variation
o Neuraminidase – destroys the cell receptors by hydrolytic cleavage
 Antigenic Variation of Influenza
- Unique feature of the influenza virus is the ability to undergo antigenic
variation
- This is of great importance in the epidemiology of the disease
- Variability is highest in influenza type A and less in type B
o It is not demonstrated in type C
- Internal RNP antigen and M protein antigen are stable but undergo
independent antigenic variations, which are of 2 types:
o Antigenic Drift
o Antigenic Shift

Antigenic Drift:

- gradual sequential change in antigenic structure, occurring regularly at

frequent intervals
- New antigens are still related to them
o Therefore they react with antisera to the predecessor virus strains to
varying degrees.
- Due to mutation and selection
o Process being influenced by the presence of antibodies to the
predecessor strains in the host population
- Accounts for the periodic epidemics of influenza

Antigenic Shift:

- Abrupt, drastic discontinuous variation in the antigenic structure

o Results in a novel virus strain unrelated antigenically to the predecessor
strains
o Such strains involve:
 Haemagglutinin
 Neuraminidase
 Or both
- Antibodies to predecessor viruses DO NOT neutralise the new variants
o it can therefore spread widely in the population, causing major
epidemics or pandemics
- Changes involved in antigenic shift are too extensive to be accounted for by
mutation.