This document discusses several human herpesviruses: - Herpes simplex viruses 1 and 2 cause oral and genital herpes. Varicella zoster virus causes chickenpox and shingles. - Cytomegalovirus commonly infects people without symptoms but can cause disease in immunosuppressed individuals. It is a major cause of birth defects. - Epstein-Barr virus causes infectious mononucleosis and has been linked to cancers. It is commonly spread through saliva. - Herpes B virus in monkeys can cause severe encephalitis in humans through bites or scratches and requires protective equipment to prevent transmission.

1. Herpesviruses. Properties of herpesviruses.
Classification. Herpesvirus infections in humans.
Herpes simplex viruses. Varicella Zoster virus;
Cytomegalovirus. Epstein Barr virus. Herpes b virus.
Paramyxoviruses and rubella virus. Rabies
Zangaladze E., MD, PhD

2. Herpesviruses
• Herpesviruses belong to the Herpesviridae -family of DNA
viruses that cause infections and certain diseases in humans.
• Nine herpesviruses are known to infect humans, five of them
are widespread
– Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2, also known as
HHV-1 and HHV-2)-both of which can cause orolabial
herpes and genital herpes;
– varicella zoster virus ( HHV-3)- the cause of chickenpox and shingles,
– Epstein–Barr virus (EBV or HHV-4) causes mononucleosis and some
cancers, and
– human cytomegalovirus (HCMV or HHV-5
• The less-common human herpesviruses are :
– human herpesvirus 6A and 6B (HHV-6A and HHV-6B),
– human herpesvirus 7 (HHV-7), and
– Kaposi's sarcoma-associated herpesvirus (KSHV, known as HHV-8).

3. Structure of Herpesviruses
• The herpesviruses are
large, enveloped viruses
that contain double-
stranded DNA.
• DNA core is surrounded by
an icosadeltahedral
capsid, which is enclosed
by a glycoprotein-
containing envelope
• Attached to the capsid and in
the space between the
envelope and the capsid are
viral proteins and enzymes
that help initiate replication.

4. Taxonomy of Herpesviruses
• Family – Herpesviridae Herpesviruses are grouped
into three subfamilies
• Subfamilies are formed on the basis of differences
in viral characteristics (genome structure, tissue
tropism, cytopathologic effect, and site of latent
infection), as well as the pathogenesis of the disease
and disease manifestation;
– 1) Alphaherpesvirinae ( HHV – 1 / HSV-1, HHV- 2/ HSV-
2, HHV-3);
– 2)Gammaherpesvirinae ( HHV – 4, HHV – 8)
– 3)Bettaherpesvirinae ( HHV-4, HHV – 5, HHV – 7).

5. Herpes Simplex Virus
• HSV-1 and HSV-2 / or HHV-1 and HHV-2 share characteristics -
DNA homology, antigenic determinants, tissue tropism, disease
signs.
The HSV genome encodes approximately 80 proteins.
– for viral replication;
– for HSV’s interaction with different host cells ,
– Coding of proteins that mediate the immune response
– coding of enzymes.
• HSV-1/ HSV-2 enter the cell: a) through the fusion of virus
envelope and the cell membrane, or (b) through the endocytosis
• HSV-1/ HSV-2 binds the cell plasma membrane with virus spike
glycoproteins gB , gC and gD; After the fusion, the capsid
transferred into the cytosol and then capsid transferred through
the cytosol to the nucleus where the capsid ejects its DNA
contents

6. Cell entry mechanisms of HSV

7. Herpes Simplex Virus (II)
• During the infection, infected cell produces virus proteins, called:
– immediate-early
– early
– late
• The immediate early gene products include DNA binding proteins,
• The early proteins include the DNA-dependent DNA polymerase
and catalytic proteins. Other early proteins initiate the degradation
of cellular messenger RNA (mRNA) and DNA.
• The late proteins form the capsid and the receptors on the surface of
the virus.
• HSVs persists in neural ganglia. HSVs persistent form known as
latent infection
• During a latent infection of neurons, the only region of the genome to
be transcribed generates the latency-associated transcripts (LATs).
These RNAs are not translated into protein but encode micro-RNAs
that inhibit expression of immediate, early and other protein genes

8. Herpes Simplex Virus(III)
• HSV-1 mainly causes oral herpes (including symptoms known as cold
sores), but it can also lead to genital herpes.
• HSV-2 causes genital herpes.
• TRANSMISSION - HSVs are transmitted by contact with an infected
person who has reactivations of the virus.
• HSV-2 is primarily a sexually transmitted infection . It can be shed in
the human genital tract, most often asymptomatically (“subclinical
shedding”). HSV-1 is often acquired orally. In some cases, it may also
be sexually transmitted
• HSV-1 and HSV-2 may also be transmitted vertically during childbirth
• SYMPTOMS- Many infected patients never develop symptoms.
• Symptoms include watery blisters in the skin or mucous
membranes of the mouth, lips, nose, or genitals; lesions heal with a
scabs. After the initial / primary infection, some infected people
Experience sporadic episodes of viral reactivation.
• Treatment – aciclovir, valaciclovir

9. Varicella zoster virus (VZV )-morphology
• Human herpesvirus 3 (HHV-
3)or varicella-zoster virus (VZV)
• DNA virus,
• genus – Varicellovirus, family –
Herpesviridae. subfamily of
alphaherpesvirus;
• Spherical virions (180–200 nm)
• DNA enclosed in the
nucleocapsid. The capsid is
surrounded by proteins known
as the tegument; The
tegument is covered by a lipid
envelope studded with
glycoproteins

10. Varicella zoster virus -VZV
• Pathogenesis -virus infects through respiratory tract.
VZV infects epithelial cells, fibroblasts, T cells, and
neurons, enters the blood , where viremia occurs, then
virus spreads through the bloodstream to skin and
causes lesions.
• Primary VZV infection results in chickenpox (varicella)
• After clinical symptoms of chickenpox have resolved,
VZV remains dormant in the nervous system of the
infected person (virus latency), and establishes latent
infection of neurons.
• Herpes zoster is a recurrent disease; Many years later,
VZV can reactivate to cause neurological conditions
herpes zoster or shingles

11. Varicella zoster virus -VZV(II)
• TRANSMISSION - VZV spreads by the respiratory route but
may also be spread through contact with skin vesicles;
incubation period 10–21 days, averages at 14 days; Patients
are contagious before and during symptoms.
• Signs and symptoms: chickenpox – high temperature, vesicles
with pus, rupture, and scab before healing. Shingles lesions
associated with pain, almost always on one side of the body
only, subside in several weeks, while the pain often persists
longer. In 10-15% of cases, a chronic condition known
as postherpetic neuralgia occurs.
• Other serious complications of varicella zoster infection
include:Mollaret's meningitis, zoster multiplex , myelitis,
herpes ophthalmicus, Ramsay Hunt syndrome

12. Varicella zoster virus -VZV(III)
• VZV infections – Acyclovir
• Herpes Zoster/Shingles - Famciclovir, Valaciclovir
• In immunosuppressed patients- varicella-zoster
immunoglobulin (VZIG)
• Prevention - A live attenuated vaccine for VZV after 2
years of age

13. Human Cytomegalovirus (HCMV) Morphology
• Cytomegalovirus (CMV) is a genus in
the family Herpesviridae,
Betaherpesvirinae.
• The 11 species in this genus
include human betaherpesvirus 5 (HCMV-
human cytomegalovirus, HHV-5),
• DNA – linear, double-stranded, non-
segmented, largest among 9 human
herpes viruses – 230-240k base pairs
• Enveloped, icosahedral, spherical to
pleomorphic; diameter 150–200 nm
• Entry into the host cell occurs
by endocytosis. involving attachment to
the cell surface, formation of endocytic
vesicles and vacuoles, delivery of viral
cargo to endosomal compartments, and
escape into the cytosol.
• Viral replication is nuclear and lysogenic.

14. Human Cytomegalovirus - HCMV
• Pathogenesis - HCMV replicates in human cells - Fibroblasts, epithelial
cells, granulocytes, macrophages; CMV replicates in the kidney and
secretory glands, so it is secreted in urine and bodily secretions.
• CMV can be found in urine, blood, throat washings, saliva, tears, breast
milk, semen, stool, amniotic fluid, vaginal and cervical secretions, and
tissues obtained for transplantation; accordingly, transmission routes
are dependent on coming into contact with bodily fluids
• Virus slow replication may facilitate the establishment of latent
infection
• HCMV infects ~60% of adults in developed countries and more than
90% in developing countries. Usually, it is controlled by a vigorous
immune response so that infections are asymptomatic or symptoms
are mild
• In most cases, CMV is shed without causing symptoms, virus rarely
causes symptoms in the immunocompetent host but causes disease in
an immunosuppressed person

15. Human Cytomegalovirus –HCMV(II)
• HCMV is the most prevalent viral cause of congenital
disease worldwide
• Signs and symptoms of congenital infection include- small
size, thrombocytopenia, microcephaly, intracerebral
calcification, jaundice, hepatosplenomegaly, and rash.
Unilateral or bilateral hearing loss and mental retardation
are common consequences of congenital CMV infection.
• The risk for congenital infection is high if the mother first
becomes infected during pregnancy. The symptoms of
congenital infection mostly can be prevented by the
immune response of a seropositive mother.
• HCMV can be responsible for development of heterophile-
negative mononucleosis syndrome, in this case the
symptoms of CMV disease are similar to those of EBV

16. Human Cytomegalovirus – HCMV(III)
• CMV spreads mainly from direct contact with
body fluids ( urine, saliva…) of infected person,
through sexual contact, tissue transplantation,
and transfusion route; accordingly, prevention
include – strict control of tissue transplantation
and blood transfusion, prevention of sexual
transmission,
• Laboratory diagnosis – serology, PCR
• Treatment – Ganciclovir, Valganciclovir ,
Cidofovir, and Foscarnet

17. Epstein–Barr virus (EBV)
• The Epstein–Barr virus (EBV)
or Human
gammaherpesvirus 4, is
a double-stranded DNA virus
• DNA is surrounded by
protein nucleocapsid, which
is surrounded by a tegument
• Viral envelope contains lipids
and glycoprteins

18. Epstein–Barr virus, EBV (II)
• EBV infects B cells and epithelial cells.
• EBV enters the host epithelial cells by fusion of host cell
membrane and viral envelope;
• fusion with B cell membranes is mediated by the viral
three-part glycoprotein complexes of gH, gL , gp42,
Viruses lacking the gp42 portion are able to bind to
human B cells, but unable to infect
• The two-part complexes of gHgL mediate epithelial cell
membrane fusion.
• Infection of children with EBV usually cause no
symptoms. When infection occurs during adolescence,
it causes infectious mononucleosis

19. Epstein–Barr virus, EBV (III)
• Signs and symptoms of infectious mononucleosis include
- fatigue, fever, inflamed throat, swollen lymph nodes in
the neck, enlarged spleen, swollen liver, or rash.
• Post-infectious chronic fatigue syndrome has also been
associated with EBV infection.
• EBV has also been implicated in several other diseases,
including Burkitt's lymphoma, Hodgkin's
lymphoma, nasopharyngeal
carcinoma, and lymphomatoid granulomatosis.

20. Epstein–Barr virus, EBV (IV)
TRANSMISSION; EBV spreads most commonly through
body fluids, especially saliva. Therefore, EBV can be spread
by using objects, such as a toothbrush or drinking glass, that
an infected person recently used. EBV can also spread
through blood and semen during sexual contact, blood
transfusions, and organ transplantations.
DIAGNOSIS - serology, molecular investigations
TREATMENT – supportive, symptomatic. no specific
treatment exists,
Prevention – no vaccine available

21. Herpes B-virus
• Herpes B-virus (Macacine alphaherpesvirus 1; McHV-1
or Herpes virus B) is very similar to HSVs
• Herpes B virus is the only identified monkey herpes
virus that displays pathogenicity in humans
• In monkeys, the virus exhibits pathogenesis similar
to that of cold sores in humans
• In humans, the virus causes severe encephalitis
• Prevention – personal protective equipment requires
when working with macaques; Bites, scratches and
exposures to mucous membranes, including the eye,
must be cleaned immediately