University of Baghdad
College of Medicine
2022-2023
Title: HERPESVIRUSES Type 1, 2, 3
Grade: Third
Module: Infectious Diseases
Speaker: PROFESSOR
DR. SAAD HASAN MOHAMMED ALI
Ph.D. VIROLOGY
Date: March 8th, 2023

University of Baghdad/ College of Medicine 2022-2023
OBJECTIVES
1.. To know the range of human diseases caused by Herpes
viruses types 1 / 2 / 3 and their virological and
immunological diagnostic facilities and control measures.
2.. To study the clinical criteria of Chicken Pox ( as a
common contagious disease in Iraq) and how to be
clinically differentiated from the serious counterpart
disease…Small Pox .
3.. To study the immunological criteria of Varicella-Zoster
Virus and how to applied these criteria in its control
measures

Herpes viruses
=Herpesviridae

University of Baghdad/ College of Medicine 2022-2023
HERPESVIRUSES
 (100 Animal species).
 ( 9 Humans species).
 Herpes Simplex Virus 1 and 2 (HHV1&2)
 Varicella-Zoster Virus (HHV3)
 Epstein-Barr Virus (HHV4)
 Cytomegalovirus( HHV5)
 Human Herpesvirus 6 (HHV6)
 Human Herpesvirus 7 (HHV7)
 Kaposi-Sarcoma Associated- Herpesvirus (KSHV) (HHV8)
 Herpes B Virus/CercoPethicine Herpesvirus-1 (CHV-1)

Classification of
Human
Herpesviruses

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Subfamily
(Herpesvirinae)
Latent
Infections
Genus
Official Name
("Human -
Herpesvirus")
Common
Name
Alpha Neurons Simplex
1 Herpes simplex
virus type 1
2 Herpes simplex
virus type 2
Varicello
3 Varicella-zoster
virus
Beta Glands, kidneys Cytomegalo
5 Cytomegalo
virus
Lymphoid tissue Roseolo
6 Human herpesvirus
6
7 Human herpesvirus
7
Gamma Lymphoid tissue Lymphocrypto
4 Epstein-Barr virus
Rhadino
8
Kaposi sarcoma-associated
herpesvirus
Herpesviridae

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Important Properties of Herpesviruses
DNA homology:
1-HSV 1 & 2 = (50%)
2- HHV 6 &7=(30-
50%)

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All= Morphologically Identical
Different herpes
viruses cannot be
distinguished by
electron microscopy
Herpes virus particles from human vesicle
fluid (X 140,000). (JAWETZ 2019)

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All =Same Characteristic Disease:

Primary Infection

LatentInfection

Reactivated Infection

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HERPES SIMPLEX VIRUSES
Pathogenesis

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Primary infections occur in childhood or adolescence…….
…..followed by establishment of latent virus in the cerebral or
spinal ganglia…….
……Later activation causes recurrent herpes simplex or zoster.
= Recurrences are rare for zoster.
Latent infections by Herpes viruses:
Examples =
Herpes simplex and varicella-zoster
viruses.

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12

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14
Herpes Simplex Virus (HSV) :
Clinical Presentation
 Primary Infection
 Prodromal phase:
Tingling/itching of skin
 Appearance of painful vesicles
in clusters on an erythematous
base
 Vesicles ulcerate then crust
over and heal within 7-14 days
 Viral shedding continues for up
to 2-3 weeks
 Recurrent Disease
 After primary infection,
virus migrates to sacral
ganglion and lies dormant
 Reactivation occurs due to
various triggers
 Reoccurrence is usually
milder and shorter in
duration

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Replication Cycle of Herpes Viruses
in General
Attachment =
-
1
Cellular Receptors = Heparan Sulphate
Fusion
-
2
Release of viral DNA

Uncoating
-
3
4- Transcription of Alpha genes  Alpha –proteins
(Cellular Preparation)
5-Transcription Beta genes  Beta- proteins =
(ENZYMES).
.
Viral DNA

Viral DNA replication
-
6
7- Transcription Gamma genes  Gamma – proteins=
=
Empty Capsids
Structural Proteins=

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Replication cycle(Continued…)
8- Packaging DNA into capsids .
10- Accumulation of viral glycoproteins on the
nuclear membrane .
11- Get Envelope from nuclear membrane .
12- VIRUSES Geat out the cell
}
Endoplasmic Reticulum
{
through

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University of Baghdad/ College of Medicine 2022-2023
Oro-pharyngeal dis
= ( HSV 1+2)
Primary infection {children }:
•
Fever + sore throat
+ vesicular & ulcerative lesions(buccal/ gingival ).
Primary infection : (adults):
*Acute pharyngitis & Acute tonsillitis ..
Recurrent lesions :
* Border of lip
1

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Oral Herpes
*Transmission is possible when lesions not
present due to viral shedding

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Oral Herpes/Cold Sores
 Transmitted by kissing and brushing against the lesion.
 They may also be transmitted by using a cup, eating
utensil,
lip gloss, toothbrush or even a face towel.
 Also transmitted to other parts of body (eye, fingers).
Life - Long Diseases

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Ophthalmic Herpes =
Kerato- conjunctivitis
blindness
 =HSV 1
1- Corneal ulcers .
2- Vesicles lesions on Eye Lids .
2
3 Genital Herpes =
=HSV2 usually :
• Vesicular & Ulcerative lesions=
• { penis , cervix , vulva, vagina , perineum ) .

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22
Genital Herpes Simplex in Females
Credit: Jean R. Anderson, MD

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Genital Herpes
Simplex
Sores
Source: Diepgen TL, Yihune G et al. Dermatology Online Atlas

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Cutaneous Herpes infection=HSV 1+ 2
A-Traumatic Herpes (Only in abrasions ) 
Herpetic Whitlow=Fingers of dentists
+ hospital personal
B- Skin infections : :
{Burns ( Fatal ) + Eczema}.
4

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Herpetic whitlow Painful, coalescing
vesicles with surrounding
erythema on fingers
history revealed that the patient regularly bit his
nails
Positive results on direct fluorescent antibody tests and viral
cultures from digital lesions confirmed type 1 HSV infection

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Eczema Herpeticum
A rare but Severe Cutaneous Herpes infection that generally occurs at sites of skin
, burns, long term usage
atopic dermatitis
damage produced by, for example,
eczema
or
topical steroids
of

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5
Most common cause of sporadic
fatal encephalitis .

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Neonatal Herpes
 Intra-uterine
 During birth ( 75%)
 After birth .
 Mortality 50%.
 Almost always= Symptomatic.
6
75% HSV 2 25% HSV 1

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Neonatal Herpes
3
Categories
Localized lesion
( skin ,eye , mouth)
Encephalitis
+- skin infection
Disseminated disease
+ death
(=pneumonitis or DIC)

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Severe infections in Immuno-
compromised patients
HSV1+2
Spread= to respiratory esophageal intestinal
tissue & other organs .
Most cases= Reactivated
Infections.
7

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METHODS TO DIFFERENTIATE
BETWEEN THE TWO TYPES OF
HERPES SIMPLEX VIRUSES

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CLINICAL LESIONS According To
Anatomical Land mark of Waist ???
ABOVE WAIST=TYPE 1
BELOW WAIST=TYPE 2
Waist
HSV 1
HSV 2
1

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Egg inoculation=Pocks size.
DNA Finger Printing=
‫فايروسات‬ ‫مه‬ ‫وىع‬ ‫لكل‬ ‫الىىوي‬ ‫الحمض‬ ‫بصمة‬
 Different Bands Size of The Two Types of HSV- DNA = by doing Restriction Enzymes analysis.
Different Serological Reactions??
No Histopathological discrimination.
No CELL CULTURE discrimination
No ELECTROM MICROSCOPICAL discrimination
5
2
3
4
6
7

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The giant cells is best illustrated by the Tzanck smear= reveals multinucleated
giant cells in a smear taken from the painful vesicles .
4 herpesviruses= HSV types 1 and 2, VZV, and CMV induce the formation of
multinucleated giant cells, which can be seen microscopically in the
lesions.
Arrow points to a multinucleated giant cell with approximately eight
nuclei

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HSV: Diagnosis
1- Clinical presentation
2-Viral culture for Isolation & identification.
3-Typing of HSV-Antigens & Nucleic acid by:
A - Monoclonal Abs B- Restriction Enzymes analysis.
4- DNA detection (PCR and ISH)
5- Serology ( IgM IgG Specific for HSV 1&2 )
6- Tzanck smear/Giemsa smear
7- Skin biopsy

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Immunity HSV 1 & 2
 Passively from the mother to baby ( 1st 6 m).
 Primary infection ( 6m – 2 years )
 Anti HSV 1 Abs = child hood & until adolescents
 Anti HSV 2 Abs = during adolescence & sexual activity
Abs  Do not prevent re-infection
or reactivation ::::::: but modify infection .
 CMI  Controlre-infection & reactivation .

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Treatment
Prevention
Control

University of Baghdad/ College of Medicine 2022-2023
Treatment of HSV-1 or HSV-2 :
 Acyclovir
 Valacyclovir
 Vidarabine
 Proved effective against HSV Infections
 All are inhibitors of viral DNA synthesis.
Suppress clinical manifestations
Shorten time to healing
Reduce recurrences of genital herpes.
 However, HSV remains latent in sensory ganglia.

University of Baghdad/ College of Medicine 2022-2023
Prevention of HSV-1 or
HSV-2 :
2…Chemoprophylaxis: Valacyclovir and Famciclovir
A… Suppression of recurrent lesions+ frequency of recurrences
B…. Reduces shedding of the virus + transmission
3… Operations:
- Cesarean section: who, at term, have genital lesions or positive viral cultures
- Circumcision: reduces the risk of infection by HSV-2
1…Avoiding contact:
with the vesicular lesion or ulcer
Still…………. No Approved Vaccines
against
HSV-1 or HSV-2

University of Baghdad/ College of Medicine 2022-2023
Varicella-Zoster
Virus

VARICELLA-ZOSTER VIRUS (VZV)
Structurally and morphologically:
similar to other
Herpes viruses
but antigenically is different.
It has a single serotype.
Disease:
The same virus causes both varicella and zoster.
Varicella (chickenpox) is the primary disease; zoster (shingles)
is the recurrent form.
Humans= Natural hosts.

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1.Varicella Virus:
 Cause Chicken pox
(((((((((‫المائي‬ ‫الجدري‬ ))))))) ((((((‫)))))ابىخريان‬
 Highly contagious disease
 Mild in children
 Severe in adults and immuno- compromized patients.
*Complications:
1.Encephalitis
 2.Pneumonia

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Chicken Pox

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
2. Zoster Virus:
= vesicles appear with severe
pain in the area of skin or mucosa supplied
by one or more groups of sensory nerves
and ganglia and is often unilateral=
=

(((((
‫جهىم‬ ‫ورد‬ ‫مه‬ ‫حزمة‬ ‫أو‬ ‫الىاري‬ ‫الحزام‬
))))))))

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Herpes Zoster
(Shingles)
Trunk
Head
Neck
are most commonly affected sites

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Complications of Zoster Virus
1…..The most common complication =Post-herpetic neuralgia—
protracted pain =for months= especially common after ophthalmic zoster.
2…. Visceral disease=especially pneumonia= in
elderly adults = deaths occur in immunosuppressed patients with zoster (<1% of
patients).
3….Varicella -zoster disease of central nervous
system, most frequently meningitis, can present with
or without a typical zoster rash.

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Herpes zoster in the distribution of thoracic and abdominal nerves

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Herpes zoster ophthalmicus
Ophthalmic division
of trigeminal nerve
involved in 10–15%

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Pathogenesis of primary infection with varicella-zoster
virus:
1.Entry :
A. Upper respiratory tract
B. Conjunctiva
2.Transmission:
A. Airborne droplet
B. Direct contact
3. Incubation period= 10 to 21 days.
4.Secondary viremia= transport of virus to skin and respiratory
mucosal sites
5. Replication in epidermal cells = characteristic rash (chickenpox).
6. VZV-specific immunity= required to terminate viral replication.
7. VZV gains access to ganglia cells= (Trigeminal + dorsal root)
establishes latency.

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Clinical Comparison
Between Chickenpox and
Smallpox

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Clinical differentiation
of chicken pox from small pox.
Causative agent Chicken pox (VZV) Small pox (Pox v.)
Severity of disease Mild Severe (mortality 1% -40 %)
Incubation period Usually 13-17 d.
(limits 10- 21d.)
Usually 11-12 d.
(limits 7- 21d.)
Distribution of rash
( density of rashes) Toward the center of body ( chest
abdomen & back)
Toward periphery of the body (head &
extremities )
Stage of rash type of rash on
time of clinical exam
Rash are seen with different
mixed stages ( papular +
vesicular rash)
All the rash at same stage &
commonly are deep set  vesicular or
pustular

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Chicken Pox in Child Patient

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Small Pox

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SMALL POX

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SMALL POX

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Clinical
Diagnosis of
VZV :
MAINLY
DEPENDABLE

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1. Isolation of VZV
2.ELECTRON Microscopic Exam:
 Herpes V. particles
3. Light Microscopic Exam:
(Tzanck smear)=
Tissues Stained with Hematoxyline and
Eosin Multinucleated Giant cells

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RAPID TESTS for VZV
4. Direct Ag Detection:
Labeled fluorescent Abs to VZV Ag. Exam. by
fluorescent microscope .
5.PCR or Nucleic Acid Hybridization:
Preferred for diagnosis of VZV encephalitis.
However, VZV DNA may be NOT detectable in CSF
at early presentation  inclusion of CSF VZV- IgM
antibodies== to improve sensitivity of diagnosis.
 6. Serological Testing=
1. Fluorescent Antibody Test
2. Elisa

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Immunity to VZV
Varicella and zoster viruses are
identical: But… the two diseases
being the result of differing host
responses.
Previous infection with varicella
=confer lifelong immunity to
varicella.
Herpes zoster= occurs in the
presence of neutralizing antibody
to varicella.

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Immunity to VZV
The VZV-specific cell mediated immunity is important in
Containment of VZV and recovery from both varicella and
zoster.
 Appearance of local interferon may also contribute to
recovery.
 Varicella-zoster virus, similar to other herpesviruses,
encodes means of evading host immune responses.
1… Down regulates major histocompatibility complex class I and II antigen
expression
2…Down regulates the interferon expression pathway

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Immunity to VZV
Infected Person
-
New Non
Person
st infected
1
st Person Same
1
Latent Infection
= Reactivated
into
Shingles
VERY
RARE
Shingles
recur
Infection
=
Chicken
Pox
First
Infection=
Chicken
Pox

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• No clear Explanation Why Reactivation of latent vzv infection
•  due to (waning of immunity)that allow viral replication in these ganglions
Varicella-Zoster Virus has 2 consecutive clinical forms that are
rarely or even not possible to recur in the same patient.

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Treatment
Effective therapy
for Varicella:
Acyclovir
Valacyclovir
Famciclovir
Foscarnet.
Ganciclovir
1… Prevent the development
of systemic
disease in varicella-infected
immunosuppressed patients
2….Halt the progression of
herpes zoster in adults.

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Treating of Patients with
zoster:
1…Accelerate healing of the
lesions
2… No cure of latent state
3… Reduce the incidence of
post-zoster neuralgia.

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No antiviral therapy is necessary for
immunocompetent children.
Immunocompetent adults with moderate or
severe chickenpox or zoster often are treated
with acyclovir =reduce the duration + severity of symptoms.
Immunocompromised children and adults
with chickenpox, zoster, or disseminated
disease= should be treated with acyclovir.

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Prevention and Control
Varicella-zoster immune globulin
(VariZIG)
= high VZV antibody titer = prevent
illness is now available for post-
exposure prophylaxis of high-risk
patients who lack serologic evidence of
immunity.

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Treatment of VZV :
Acyclovir
Famciclovir
Valacyclovir
Foscarnet= Acyclovir-resistant
strains of VZV

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A live attenuated varicella vaccine =
In 1995=
A single dose = highly effective protection from
varicella: in children= (80–85% effective) but in
adults(70%).
In 2006=
Two doses = 98% effective prevention of
varicella disease in children.
Duration of protective Antibodies = least 20 years.

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Herpes Zoster (Shingles) Vaccine
 Licensed in USA in 2006.
14 times more potent version than varicella vaccine.
 Effective in older adults = reducing both
1…frequency of outbreaks of zoster
2…severity of disease
Recommended :
 Chronic medical conditions
Persons older than 60 years of age.

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Prevention of VZV:
1..Vaccines
2..Immunoprophylaxsis
3..Drugs

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Two vaccines against VZV=
 BOTH= live, attenuated VZV, but the zoster vaccine contains 14 times more virus
than the varicella vaccine
 BOTH = should not be given to immuno-compromised people + pregnant
women
 1.. Varicella vaccine= to prevent varicella= Varivax= Two doses.
 recommended for children between the ages of 1 and 12 years 2.. Zoster
vaccine= to prevent zoster= Zostavax= one dose.
 A…Recommended for people older than 60 years and who have had varicella.
 B… effective in preventing the symptoms of zoster, but does not eradicate the latent state of VZV.
 Varicella-zoster immune globulin (VZIG)=
 Contains a high titer of antibody to the virus, is also used for such prophylaxis.
 Acyclovir= useful in preventing varicella and dissemination of zoster in immunocompromised
people exposed to the virus.

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THE SUMMARY
 1.. Herpes simplex viruses type 1&2 are associated with a
range of human diseases that are difficult to be clearly
attributed to any type of them.
 2.. Chicken Pox as a common contagious disease in Iraq can
be diagnosed and differentiated from Small Pox on clinical
as well as virological criteria.
 3..Varicella-Zoster Virus has 2 consecutive
clinical forms that are rarely or even not
possible to recur in the same patient.

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Thank you