Transcript Lifelong latent infection.

Herpesviruses
General characteristics of Herpesviridae
 1. most important human pathogens (HSV, VZV, EBV…), some wide host cell
range (HSV), others have narrow host cell range (EBV).
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2. different types of infection
I - Primary infection
-1st attack in person.
- clinically asymptomatic.
- followed by latent infection.
II - Latent infection
- Lifelong latent infection.
- Neurons (HSV,VZV) or lymphocytes (EBV, CMV).
III - Secondary infection (recurrent infection)
Occur individuals those exposed to virus previously & have virus latent in the
body.
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3. Herepsviruses susceptible to antiviral chemotherapy because they are large
viruses, more independent of cellular function & there is more virus specific
process are available as target for drug action.
 4. Virus Spherical in shape enveloped , large size
viruses(150-200)nm
in
diameter,
enveloped
icosaherdral in symmetry.
 5. Genome double-stranded DNA, linear, 125-240 kbp.
 6. Replication: nucleus.
 7. Herpesviruses have been linked with malignant
diseases in human:
a- EBV with Burkitt´s lymphoma, &
nasopharyngeal carcinoma.
b- HHV8 associated with Kaposi sarcoma.
Note that all
herpesviruses have
identical morphology
and cannot be
distinguished from
each other under
electron microscopy.
Classification of herpes viruses
I-
α -Alpha herpes viruses
three subfamilies
HSV-1
HSV-2
VZV
Characterize by
a- Wide host range.
b- Efficient replication, cultivated easily in vitro.
c- Establish latency in sensory ganglia ( neurons).
2- β-Beta herpes viruses
CMV
HHV6
HHV7
Characterize by
a- Narrow host range.
b- Slow replication, enlargement of the infected cells.
c- Site of latency secretary glands, kidney, lymphoid tissue.
3- γ- Gamma herpes viruses
EBV & HHV8
Characterize by
a- Narrow host range.
b- Ability to transform cell.
c- Latency in lymphoid cell lines, but when infect epithelial cell
cause replication not latency.
Herpesviruses commonly infect humans:
 1- Herpes simplex virus (HSV)
- HSV1 cause primary oropharyngeal herpes.
- latent in trigeminal ganglion.
- cause recurrent attacks of fever blisters.
- HSV 2 cause primary genital herpes.
- latent in dorsal root ganglion.
- recurrent lesion in the genital tract.
 2- Varicella- Zoster virus (VZV)
- Primary infection cause chickenpox (varicella)
- Latent infection in neurons.
- Reactivation cause zoster (shingles).
 3- Epstein- Barr virus (EBV)
- Primary disease is infectious mononucleosis.
- Latent infection in B lymphocytes.
- Reactivation occur as asymtomatic virus excretion in saliva.
 4- Cytomegalovirus (CMV)
- Primary disease in adolescent infectious mononucleosis
(heterophil negative).
- Newborn cause congenital defects & mental retardation if occur
during intrauterine life.
- CMV establishes lifelong latent infections.
- Reactivation occur as asymptomatic virus excretion or as serious
infection like CMV pneumonia in immunocompromised.
 5- Human herpesvirus 6 & 7 (HHV6, HHV7)
- HHV6 infect lymphocytes in early infancy.
- exanthema subitum ( roseola infantum ), febrile illness of children
with maculopapular rash.
- Target cells are not known.
HHV7 T lymphotropic virus has not yet been linked to any specific
disease (closely related to HHV6).
 6- Human herpesvirus 8 (HHV8) associated with Kaposi´s sarcoma
common among patients with AIDS.
 7- Herpes B virus of monkeys is highly pathogenic for humans.
Transmissibility of virus to humans is limited, but infection when
occur are associated with high mortality rate ( ~ 60%). B virus
disease of humans is an acute ascending myelitis &
encephalomyelitis.
Herpes Simplex Virus (HSV)
Introduction
HSV infection widespread, replicate in many types of cells (epithelial cells of
oropharynx, eye, genital tract, neurons), virus grow rapidly .
HSV establish latent infections in nerve cells, & recurrence are common.
 Properties of virus: spherical, enveloped, with icosahedral nucleocapsid,
genome is double stranded DNA with 150 kbp.
Types of Herpes simplex virus
 Two distinct types
HSV1.
HSV2 .
Differences between two types
 a- The genome sequence homology similar is 80% , distinguished by restriction
enzyme analysis of viral DNA.
 b- The two viruses cross react serologically, but unique proteins exist for each
type ( specific antigen).
 c- Mode of transmission.
HSV1 spread by contact with infected saliva.
HSV2 is transmitted sexually or from a maternal genital tract to newborn.
Pathogenesis of herpes simplex infection
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Source
Human with symptomatic or asymptomatic infection.
Mode of transmission
HSV1 the virus is transmitted by respiratory droplets or by direct contact
with infected saliva .
HSV2 transmitted by contact with genital secretion.
Spread
Viral replication occur first at the site of infection (local lesion), then invade
local nerve endings & transported retrogradly to axonal flow to reach the
site of latent infection in neuronal ganglion.
HSV latent infection
Site: HSV1 trigeminal ganglia, HSV2, sacral ganglia.
State: virus resides in infected ganglia in non replicating state.
Period: ( life long latency).
Eradication: Virus cannot be eradicated from the host even by antiviral
drugs.
Reactivation
Spontaneously or following stimuli (axonal injury, fever, physical stress,
emotional stress, exposure to UV, menstrual cycle, immunosuppresion).
Immunity in the host limits local viral replication so that lesion are less
extensive & less sever.
 Spread after reactivation
Virus follows nerve axons back to the peripheral site
and replication proceeds in the skin or mucous
membrane (vesiculo-ulcerative lesion).
HSV1 to oral mucosa, eye.
HSV2 genital mucosa.
Clinical disease (HSV1, HSV2)
I. Oropharyngeal disease
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1- Primary HSV-1 infection
Children ( 1- 5 years)
- herpetic gingivostomatitis.
- I.P
3-5 days.
- fever, sore throat.
- vesiculo-ulcerative lesions of buccal & gingival mucosa &
submandibular lymphadenopathy.
Adults
- herpetic pharyngitis & tonsillitis.
- Localized lymphadenopathy.
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2- Recurrent infection
- herpes labials (fever blister).
spontaneous reactivation or following certain stimuli (fever,
stress, menses).
- Lesion localized at border of the lip.
- pain occur at the onset & lesion appear as a cluster of
vesicles.
- Progress through pustular lesion & crusting stage, heal
without scarring in 8-10 days.
Primary herpes
simplex virus
gingivostomatitis
in a child,
extending to
involve the cheek,
chin and
periocular skin.
II. Keratoconjunctivitis
 Primary infection
with HSV-1 occur in the eyes producing, sever kerato conjunctivitis
(red eye with pain).
 Recurrent lesions
occur as denderitic keratitis, common appear as corneal ulcer or as
vesicles on the eyelids.
Recurrent herpetic keratitis cause permanent corneal opacity &
blindness.
III. Genital herpes
 Primary genital herpes
Acquired sexually & can be sever lasting for 3 weeks.
Most cases caused by HSV2.
vesiculo-ulcerative lesions of male genitalia, & female - cervix,
vagina & perineum.
Lesion is very painful with fever & inguinal lymphadenopathy.
Viral excretion persist for about 3 weeks.
The virus become latent in sacral ganglion.
 2- Recurrent genital herpes
Common & tend to be mild (vesiculo-ulcerative lesion of genital
tract), virus excretion last for few days.
Recurrence may be asymptomatic presented with virus excretion.
IV. Skin infections
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1- Localized infection
herpes caused by HSV-1 or HSV-2, as a result of abrasions contaminated
with virus.
Lesion seen in the figures of dentists & hospital personnel (contaminated
with saliva) herpetic whitlow & body of wrestlers ( herpes gladiatorum).
 2- Generalized infection
Sever & life threatening condition in individuals with skin disease such as
eczema (Eczema herpeticum) or burns that permit viral replication & spread.
There is high fever & extensive vesiculation of skin over large area .
V. HSV Encephalitis
Sever form of encephalitis (mostly HSV1 lesser HSV2), mortality 80%
without treatment.
 This infection may be primary or recurrent from latent virus.
 In adults & older children the neurological manifestation suggest a
lesion in the temporal lobe, pleocytosis chiefly lymphocytes in CSF.
 Diagnosis needed urgently
abcd-
Immunofluorescent test is the method of choice.
Hybridization using labeled DNA probes.
PCR will provide rapid results.
Serology by measure IgM in CSF or serum.
VI. Neonatal herpes simplex infection
 Primary infection of neonates with HSV, results in sever herpetic
disease (mortality is 50%) because of inability to limit viral
replication & spread (immature immunity).
 About 75% of neonatal herpes infection caused by HSV-2.
 Source newborn acquire the infection
 1- Prenatally during intrauterine period.
2- Natally ( ≥ 75%) during delivery, contact with herpetic lesions
in birth canal.
3- Postnatally acquired through exposure to HSV-1 or HSV-2
from family members & hospital personnel .
 Neonatal herpes
almost always symptomatic, three forms
1- Lesion localized to skin, eye, & mouth.
2- Encephalitis with or without localized skin involvement.
3- Disseminated disease involving multiple organs including CNS,
mortality 80% & those survive left with permanent neurological
deficit.
The cause of death of babies with disseminated disease is usually
viral pneumonitis or intravascular coagulopathy.
VII. Infection in immunocompromised patients
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Sever HSV infections occur among patients with impaired immunity like
those with cytotoxic therapy, transplants patients, haematological
malignancies, & those with AIDS.
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Mortality > 80%.
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Most disease reflect reactivation of latent HSV infection.
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Clinically the disease presented as
1- Respiratory tract ( HSV pneumonia).
2- Intestinal mucosa, liver (HSV hepatitis).
LABORATORY DIAGNOSIS
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1- General cytological changes
scraping or swab from the base of lesion contain
multinucleated giant cells that are indicative for HSV
infection.
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2- Direct detection
a- Electron microscopy of vesicle fluid, show virus
particles.
b-Immunoflouresent stain of swab from the skin lesion
c-PCR, used routinely for the diagnosis of herpes simplex
encephalitis
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3- Isolation & identification of virus
Samples from throat wash, skin, eye, brain, genital lesions.
Inoculated onto cell monolayer (HEP-2) & monitored for
the development of characteristic cytopathic effect
(swollen & rounded cells in cell culture.
This is usually detected within in 2-3 days.
Positive immunofluorescence test for
HSV antigen in epithelial cell.
The virus can be further identified by immuno
fluorescent staining with specific antiserum.
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4- Serology
Specific antibodies appear in 4-7 days after infection.
Tests CF, RIA, ELISA.
measurement of type specific antibodies (rising titer of
IgG, or specific IgM) .
Cytopathic Effect of HSV in cell culture
HEP-2: Note the ballooning of cells.
LABORATORY DIAGNOSIS
Positive immunofluorescence test for
HSV antigen in epithelial cell.
Cytopathic Effect of HSV in cell culture
HEP-2: Note the ballooning of cells.
Treatment
 Several antiviral drugs proved effective against HSV infection, all are
inhibitors of viral DNA synthesis through inhibition of viral
polymerase.
 It inhibit herpesvirus replication & suppress clinical manifestation.
 Types of antiviral drugs
 1- Acyclovir:
Non toxic drug, it is used locally, orally, intravenously.
Drug of choice for treatment of the following herpetic conditions:
A- Herpes encephalitis.
B- Herpetic keratitis.
C- Ezema herpeticum.
 D- Immunocompromised.
 2- Vidarabine effective for herpes infection, but is more toxic used to
treat infection caused by acyclovir resistant isolates of HSV.