University of Balamand

Faculty of Medicine and

Medical Sciences

CVIR401
Lecture#3
Herpesviruses

Instructor: Samer Bazzi, PhD

 Herpesviruses
General Characteristics
- Herpesviruses are a leading cause of human viral diseases, second only to influenza
and common cold viruses
- Classification: the herpesvirus family, Herpesviridae is divided into 3
Herpesvirinae subfamilies:

Subfamily Genus Main Species

Simplexvirus Human herpesvirus 1, 2 (HHV-1/HSV-1,
Alpha HHV-2/HSV-2)
Varicellovirus Human herpesvirus 3 (HHV-3/VZV)
Cytomegalovirus Human herpesvirus 5 HHV-5/CMV)
Beta
Roseolovirus Human herpesvirus 6, 7 (HHV-6, HHV-7)
Lymphocryptovirus Human herpesvirus 4 (HHV-4/EBV)
Gamma
Rhadinovirus Human herpesvirus 8 (HHV-8/KSHV)
 Herpesviruses
General Characteristics
- Huge dsDNA viruses
- Structure
 Envelope: lipid bilayer with numerous glycoproteins
 Tegument: a protein-filled region containing transcription and regulatory factors
 Nucleocapsid: Icosahedral, dsDNA genome surrounded by a proteinaceous core.
- Host Receptors include: Heparan
sulfate, Nectin, DC-SIGN, and CD21.

- Replication and virion assembly occur

in nucleus.

- Herpesviruses are unique in acquiring

their envelopes by budding through
nuclear membranes.

- Virions are transported and released

via exocytic vesicles.
 Herpesviruses
General Characteristics
- Depending on virus and host cell parameters, infection with herpes viruses may
result in lytic, in persistent, or in latent infection.
- Most herpes viruses encode enzymes such as: 1) thymidine kinase (TK) that allows
virus to grow in non-dividing cells (nerve cells) and 2) ribonucleotide reductase
which converts ribonucleotides to deoxyribonucleotides.
- In latently-infected neurons, virus DNA resides as circular unintegrated DNA in
cell cytoplasm or nucleus. Transcription becomes limited to generate “latency-
associated transcripts (LAT)” which are noncoding regulatory RNAs that suppress
viral replication.
 Herpes Simplex Virus-1/2 (HSV-1/HSV-2)
General Characteristics
- Two closely related viruses, second in size to poxviruses.
- HSV-1 is usually associated with oro-facial lesions and HSV-2 with genital lesions.
Infection with HSV-1 is universal (nearly 100% of adults have Abs in serum).
- Few glycoproteins are essential for:
i- virus egression and cell-to-cell spread: gG and gK
ii- inducing neutralizing Abs: gB
iii- immune escape: gC (binds C3 and depletes it from serum  inhibition of
complement-mediated reactions)
iv- binding Fc portion of IgG: gE and gI complexes (hide virus from immune
attack) Macule Papule
Pathogenesis
- Infect humans and animals, but only humans
show symptoms

- Infects mucosal epithelial cells or enters through

wounds in the skin
- Following virus replication, a reddened area
gives rise to a macule, a papule, and then to a
vesicle containing fluid full of infectious virus. Vesicle
Vesicles then heal and usually no scar is evident.
 HSV-1/HSV-2
Pathogenesis
- Infects innervating neurons and travels
along neurons to reach trigeminal ganglia
(HSV-1, in case of oral mucosa infection)
or sacral ganglia (HSV-2, in case of
genital mucosa infection) leading to a
latent infection.
- Break of latency may occur and virus can
travel down the nerve axon leading to
recurrences (lesions in skin) at the same
site of initial infection. Recurrences can be
triggered by stress, strong sunlight, or fever
and are less pronounced than primary
infections.
TG: trigeminal ganglia
- Also infects macrophages and SG: sacral ganglia
lymphocytes. Virus presence is indicated
by syncytia formation and cowdry type A
inclusion bodies in the nucleus. Infection
of endothelial cells and fibroblasts leads to
lytic infection but that of neurons leads to
latent infection Cowdry type A
 HSV-1/HSV-2
Host Immune Response
 Interferon and NK cells play a key role in limiting infection
 CTLs and macrophages kill infected cells and together with an inflammatory response
may lead to some of disease symptoms.
 Abs directed to surface glycoproteins (gB) can lead to neutralization, but virus may
escape by coating itself with IgG (via gE and gI)
 Virus can spread from one cell to another without entering extracellular space and being
in contact with Abs (via gG+gK)
 Immunity to HSV is mediated by Th-1 cytokines and activated innate immunity
 Reactivation occurs with increased Th-2 cytokines (IL-10), increased Tregs, and
inhibition of IFN-induced NK cell activation. The ribonucleotide reductase protein is the
key Th-2 polarizing Ag implicated in HSV replication and latency break.
 HSV-1/HSV-2
Transmission/Epidemiology
 HSV-1 and HSV-2 infections are life long; transmission to other subjects is mostly
observed during recurrences. Incubation period is 2-10 days.

 Virus is found in skin lesions and body fluids (saliva or vaginal secretions)

 HSV-1 is usually spread mouth to mouth (kissing), or by transfer to hands after which
virus enters via wounds or eyes.

 HSV-2 is usually spread sexually, is present in the anus, rectum, upper GI tract and
genital areas. However, oro-genital sexual practices can result in HSV-1 infection of
genitals and of HSV-2 lesions in the oral cavity (10-20% of cases and up to 40% in
western countries)

 HSV infection may be transmitted from mother to infant perinatally and rarely in
utero.

 Reactivation can occur in the presence of IgG anti-HSV Abs

 HSV-1/HSV-2
Clinical Significance
1- Gingivostomatitis
- Common form of primary infection in children, inoculation through saliva, and with
spectrum of severity.
- Painful vesicles develop on buccal mucosa and gums, on lips, tongue, skin and eyes.
- Primary eruption is associated with fever and cervical lymphadenopathy.
- Illness is self-limiting within 14-20 days.
- A recurrent presentation is known as Oral Herpes (Herpes Labialis) which is less
severe (cold sores) than primary eruptions
Gingivostomatitis Herpes Labialis
 HSV-1/HSV-2
Clinical Significance
2- Kaposi’s varicelliform eruption 3- Herpes whitlow
(eczema herpeticum) - Inoculation of HSV1 into fingers via
- Superinfection of eczematous skin with small wounds
HSV, occurs frequently in children - An occupational hazard of doctors,
nurses and dentists
- May be caused by transfer of HSV-2
from genitals to fingers or hands
Clinical Significance HSV-1/HSV-2
4- Herpes Gladiatorum/Rugbeiorum
- Contracted by wrestlers/rugby players
- Vesicular lesions appear in head, neck and
trunk.

5- Herpes Keratoconjunctivitis
- Eye infection (mostly HSV-1) with corneal
ulcers, lesions of conjunctival epithelium, and
photophobia. Upon recurrences, it may lead to
blindness

6- HSV Proctitis
- Inflammation of rectum and anus

7- HSV Encephalitis
- Infection of brain with involvement of temporal
lobe neurons; infection is severe/necrotizing and
is associated with blood in CSF, fever, confusion,
and seizures. Mortality is high!
Clinical Significance HSV-1/HSV-2
8- Herpetic Sycosis
- Affecting mainly hair follicles

9-HSV-2 Meningitis
- Symptoms resolve spontaneously

10- Herpes Esophagitis

- Painful swallowing or difficulty in
swallowing (dysphagia)
- Often associated with impaired CMI as in
AIDS cases

11- Genital Herpes

- Sexually transmitted herpetic lesions
(mostly HSV-2)
- Primary infection may be asymptomatic, but
painful lesions can develop on glans or shaft
of penis and on vulva, vagina, cervix and
perianal regions.
- Primary eruption lasts 10-14 days, involves
transient viremia (may be accompanied by
fever, myalgia)
Clinical Significance HSV-1/HSV-2
12- HSV Infection of Neonates
- Mostly caused by HSV-2
- Rare but fatal

- The baby is usually infected perinatally, during passage through the birth canal, and
the risk is greatest when there is a primary infection in the mother.

- Lower risk of transmission in case of recurrent lesions in the mother.

- Premature rupturing of the membranes is a well recognized risk factor and the baby
may also be infected from other sources such as oral lesions in the mother or a herpetic
whitlow in a nurse.

- Spectrum of neonatal HSV infection varies from a mild disease localized in the skin to
a fatal disseminated infection with particular danger in premature infants. The organs
most commonly involved are the liver, adrenal glands and the brain (prognosis is
particularly poor with encephalitis and the brain may be liquefied).
 HSV-1/HSV-2
Laboratory Diagnosis
- Cells from vesicles can be stained with Giemsa (Tzanck smear) and the presence of
multinucleated cells suggests HSV infection

- Immunofluorescence on skin scrapings, to detect viral antigens, can distinguish

between HSV and VZV.
- PCR is now used routinely for the diagnosis of herpes simplex encephalitis

•Virus Isolation
- HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes only 1-3
days for a result to be available.

•Serological testing
- Limited use in the acute phase (takes 1-2 weeks before antibodies appear after
infection). Not useful in detecting recurrences since adults have circulating Abs and a
rise in titer rarely occurs.
Treatment
HSV-1/HSV-2
- Nucleoside analogs which take advantage of drug activation by viral TK.
Phosphorylated drugs inhibit viral DNA polymerase and are more active against viral
than against cellular polymerases.

- Drug becomes activated only in infected cells  low side effects; compete with GTP
and act as chain terminator of viral DNA synthesis.

- Best drug is Acyclovir (acycloguanosine) or Zovirax given i.v., orally, or as a cream.

For the oral route, Valacyclovir (L-valyl ester prodrug of acyclovir) is frequently used
and presents higher bioavailability and serum levels than oral acyclovir.

- Acyclovir should be promptly given in all suspected cases of neonatal HSV infection.
Prevention
- C-section for HSV-2 infected women
- Use of condoms and dental dams during oral, anal, and vaginal sex
- Glove wearing and washing hands with soap
Vaccine
- No available vaccine
 Varicella-Zoster Virus (VZV, HHV-3)
General Characteristics
- Zoster means girdle from the characteristic rash that forms a belt around the thorax
- Structure similar to HSV, but with smaller genome
- Infection with VZV can lead to 2 clinical entities:
1- Varicella or chicken pox, a primary infection in childhood
2- Shingles (also known as herpes zoster), a recurrence later in life

Transmission/Epidemiology
- Primary varicella is an endemic disease with the highest prevalence occurring in the 4
to 10 years old children. It is highly communicable with 90% attack rate in close
contacts.
- Most people (90%) become infected with chicken pox before adulthood and the virus
is transmitted by respiratory droplets or by direct contact with the lesions.
- Shingles occurs sporadically, mostly in adults, and results from virus reactivation.
 Varicella-Zoster Virus (VZV, HHV-3)
Pathogenesis
- Following infection, virus starts replicating in nasopharynx and in regional lymph
nodes, and by days 4-6, a primary viremia is detectable.

- Virus spreads to the liver, spleen, and other organs where it replicates and leads to a
secondary viremia by day 10

- Virus spreads via the blood to the skin where typical vesicular rash develops by day 14
post-infection.

- Virus also infects sensory neurons and is carried, by axonal transport, into cells of the
dorsal root ganglia where it becomes latent with unintegrated viral DNA in the
nucleus. Upon future deficits in CMI or due to local trauma, virus becomes re-
activated and causes shingles with painful vesicular skin lesions.
Clinical Significance Varicella-Zoster Virus (VZV, HHV-3)
1- Chicken Pox (primary infection)
 Incubation period is long (14-21 days).
Varicella
 Disease presents as mild febrile illness
associated with generalized vesicular Primary
asynchronous rash Rash
 Lesions progress from macules to papules to
vesicles to pustules, and finally crust to form
scabs. Itching is prominent.
 In children, complications are rare; in adults,
disease can be severe with complications
(pneumonia and encephalitis). Reye’s
syndrome is also associated with VZV and
influenza B infections, specially in children Varicella
receiving high aspirin dose. Primary
 Varicella is followed by long lasting immunity Lesions
 Complications of chicken pox: hemorrhagic
varicella; fulminating infection in
immunocompromised patients with high
fatality rate
 Varicella-Zoster Virus (VZV, HHV-3)
Clinical Significance
2- Congenital Varicella Syndrome
 Occurs in infants born to mothers who develop varicella in early pregnancy.
 Rare condition associated with limb hypoplasia, muscular atrophy, mental
retardation and skin scarring.

3- Perinatal varicella
 If mother develops varicella more than 5 days before delivery:
- Disease is mild in infant and controlled by maternal Abs.
 If mother develops varicella less than 5 days before delivery:
- Neonate is likely to develop severe disease with fatal varicella pneumonia.
- Administration of special hyperimmune globulin (Zoster Ig) to the baby is
necessary.
 Varicella-Zoster Virus (VZV, HHV-3)
Clinical Significance
4- Shingles (Herpes Zoster)
 VZV establishes a latent infection in
sensory ganglia

 Reactivation occurs several years

after primary infection and is
associated with host
immunosuppression

 Virus travels down the axon and re-

infects the dermatome supplied by
the sensory ganglion to produce
painful vesicles on skin. Common Shingles
sites include thoracic dermatomes
and those supplied by trigeminal
nerve

 Post-herpetic neuralgia is a common

complication
 Varicella-Zoster Virus (VZV, HHV-3)
Clinical Significance
4- Zoster/Shingles
 Varicella-Zoster Virus (VZV, HHV-3)
Laboratory Diagnosis
- Tzanck smear can be used (Giemsa stain of cells in vesicles reveals giant
multinucleated cells) or isolation in cell culture.
- Virus is now detected by PCR.

Treatment
- Severe symptoms are treated with acyclovir or oral valacyclovir.
- Resistant strains can be treated intravenously with Foscarnet (non-nucleoside
pyrophosphate analogue inhibiting pyrophosphate binding to viral DNA polymerase
and not requiring activation by vTK).
 Varicella-Zoster Virus (VZV, HHV-3)
Vaccine
- Active immunization: Live attenuated VZ vaccines are safe and effective in children
and adults.
• Varivax: varicella virus given to children 1-12 years of age (3 s.c. administrations)
to protect against chickenpox.

• Zostavax: virus given as single injection (s.c.) to people who have had chicken pox
and are ≥60 years of age to prevent the symptoms of shingles. Vaccine contains 14
times the virus dose used in varivax

• The above 2 vaccines contain live virus and should not be given to
immunocompromised (IC) people or to pregnant women

• A new vaccine, Shingrix, was approved in 2017 and gave 97% efficacy in
preventing shingles in people above 50 years of age. Unlike Zostavax, this vaccine
consists of gE with liposomal-based adjuvant. Given i.m. on days 0 and 60 even to
IC subjects.
 Varicella-Zoster Virus (VZV, HHV-3)
Prevention
Targeted for individuals who are at risk of contracting severe forms of the disease:
- Antiviral drugs – Acyclovir is used in immunocompromised hosts. A 7-day course, 40
mg/kg in divided doses, is given 7-9 days after virus contact

- Passive immunization – Zoster Ig prepared from selected donors with high titer Ab to
VZV. Needs to be administered within 96 hours of contact. Mostly aimed for pregnant
women who come in close contact with VZV at any stage of pregnancy.
 Epstein-Barr Virus (EBV, HHV-4)
General Characteristics
- Genome is large coding for over 100 proteins and the dsDNA forms unintegrated,
circular episomes that reside in the nucleus.

Transmission/Epidemiology
Two epidemiological patterns are observed with EBV:
- In developed countries, 2 peaks of infection are seen: the first in very young children
aged 1-6 years (mostly asymptomatic) and the second in adolescents and young adults
aged 14–20 years (frequently with clinical disease). Eventually 80-90% of adults
become infected.
- In developing countries, infection occurs at a much earlier age so that by the age of
two years, >90% of children are seropositive.
- The virus is mainly transmitted by contact with saliva, particularly through kissing.
Blood transmission of EBV has been rarely reported.
 Epstein-Barr Virus (EBV, HHV-4)
Pathogenesis
- Once infected, a lifelong carrier state develops whereby a low grade infection is kept in
check by the immune defenses. Virus replication and shedding can be continuously
demonstrated in all seropositive individuals.
- Cells permissive for EBV infection (via CR2/CD21) include epithelial cells of oro- and
naso-pharynx (presenting lytic infection) and B lymphocytes which are only semi-
permissive for EBV, leading to latency.

- EBV is able to immortalize B-lymphocytes in vitro and in vivo and few immortalized B-
cells can be demonstrated in the circulation. These are continuously cleared out by
immune surveillance mechanisms.
- EBV is associated with different diseases where it may be the direct cause or may act as
one of several co-factors.
 Epstein-Barr Virus (EBV, HHV-4)
Clinical Significance
1- Infectious Mononucleosis (IM)
- A clinically apparent illness mostly develops when primary EBV infection occurs in
adolescence or young adulthood. Incubation period is 4-7 weeks and virus is shed in saliva
of asymptomatic individuals.
- Signs and symptoms: swollen tonsils, extreme fatigue, rash, sore throat, headache,
splenomegaly, swollen liver, lymphadenopathy

- Spontaneous recovery occurs in 2-3 weeks but convalescence may be prolonged in some
cases (>6 months)
- Complications include neurological disorders (Guillain-Barré syndrome), anemia, and
thrombocytopenia.
 Epstein-Barr Virus (EBV, HHV-4)
Clinical Significance
Amoxicillin rash in a patient with
EBV-related tonsillar exudate
infectious mononucleosis
 Epstein-Barr Virus (EBV, HHV-4)
Clinical Significance
2- EBV-associated Hemophagocytic Syndrome (EHS)
- A condition common in Southeast Asian children arising from EBV infection of T
cells or/and NK cells leading to acute fatal endpoint with complete destruction of
lymphoid tissues by activated macrophages.
- Alternatively, a chronic infection could develop with recurrent IM-like symptoms,
high levels of IFN-γ and TNF-α in plasma, and a large expansion of EBV-positive T or
NK cell clones in peripheral blood.

3- Lymphoproliferative disorders
- Immunosuppressed patients (transplant patients) and those with T-cell deficiency
develop polyclonal proliferation of EBV-transformed B cells.

4- Hairy Leukoplakia
- Lesions and lymphomas may develop in unusual sites such as GI tract or CNS. In
AIDS patients, EBV is associated with hairy leukoplakia.
 Epstein-Barr Virus (EBV, HHV-4)
Clinical Significance

EBV-Related Scrotal Ulceration EBV-Related Hairy Leukoplakia

 Epstein-Barr Virus (EBV, HHV-4)
Clinical Significance
5- Burkitt’s lymphoma (BL)
- High grade B cell lymphoma occurring sporadically worldwide, and endemically in
Equatorial Africa and New Guinea.
- Patients have high level of Abs to EBV, EBV genome is detected in tumor cells and
virus particles are detectable in cultured BL cells.

6- Nasopharyngeal carcinoma (NPC)

- Malignant tumor of squamous epithelium of nasopharynx. Undifferentiated form of
this tumor is associated with EBV. Patients present Abs to EBV, EBV genome is
present in NPC, and virus can be recovered from cultured NPC cells.

7- Hodgkin and non-Hodgkin lymphoma

 Epstein-Barr Virus (EBV, HHV-4)
Clinical Significance
Diseases associated with EBV infection
Lymphoid Epithelial
Burkitt’s lymphoma Nasopharyngeal carcinoma
B-cell immunoblastic lymphoma*
Parotid carcinoma
T-cell lymphoma
Hodgkin’s disease Gastric carcinoma
Chronic interstitial lymphocytic pneumonitis* Oral leukoplakia*
XLPS* Lymphoid and epithelial
EHS* Infectious Mononucleosis*
Other
Leiomyosarcoma

‫٭‬Reflects diseases in which EBV plays a direct causal role.

- In all other diseases, EBV is judged to play essential, cofactor, or a clonal association
role.
 Epstein-Barr Virus (EBV, HHV-4)
Laboratory Diagnosis
 Paul Bunnell test based on detection (in 70-80% of patients) of IgM heterophilic Abs that
agglutinate sheep RBCs. These Abs, appearing by week 2 post-infection, can be absorbed on
beef red cell stroma  Monospot test (more sensitive and specific than Paul Bunnel test-
uses horse RBCs).
 EBV-specific Ab test: IgM against viral capsid antigen (VCA) can be used to diagnose
early illness.
 Absolute lymphocytosis occurs
and blood smears show atypical
lymphocytes, Downey cells, with
lobulated nucleus and a vacuolated
basophilic cytoplasm. These are
CD8 Tc cells activated by the
infected B cells.

Downey
cell

 PCR to detect viral genome.

 Epstein-Barr Virus (EBV, HHV-4)
Treatment
- No treatment is highly satisfactory; best promise with oral Valacyclovir.

Vaccine
- No vaccine is yet available
Epstein-Barr Virus (EBV, HHV-4)
 Cytomegalovirus (CMV, HHV-5)
General Characteristics
- Human CMV has a single serotype and humans are the natural hosts.
- Infection leads to Giant cell formation, hence the name “cytomegalo”.

Transmission/Epidemiology
- CMV is one of the most successful human pathogens, it can be transmitted vertically
or horizontally, and usually, with little effect on the host.
- Early in life, it is transmitted across the placenta, within the birth canal, and quite
commonly in breast milk.
- In young children, transmission is mainly through saliva.
- Later in life, it is transmitted sexually (present in semen and cervical secretions),
through blood transfusions, or by organ transplants.
- Once infected, the person carries the virus for life. It may be activated from time to
time to give infectious virions in the urine and saliva.
- In developing and developed countries, infection with CMV is detected in 80-90%
of the population.
 Cytomegalovirus (CMV, HHV-5)
Pathogenesis
- Human CMV infects salivary gland epithelial cells and establishes a persistent
infection in fibroblasts, epithelial cells and macrophages (latency in mononuclear cells)
 Cytomegalovirus (CMV, HHV-5)
Clinical Significance
-Infection of the fetus (most frequently due to a primary infection of the mother) may result
in cytomegalic inclusion disease with severe congenital abnormalities detected if infection
occurs during the first trimester of pregnancy. May also be transmitted to the fetus during
late stages of pregnancy but with no evidence of teratogenicity.

- Congenital infection is determined by the isolation of CMV from the saliva or urine within
3 weeks of birth. Most common congenital viral infection affecting 0.3-1% of all live births.

- Clinical manifestations can affect:

 CNS (microcephaly, mental retardation, and epilepsy)
 Eye (chorioretinitis and optic atrophy)
 Ear (sensorineural deafness)
 Liver (hepatosplenomegaly and jaundice/hepatitis)
 Lung (pneumonitis)
 Heart (myocarditis)
 Immune System (thrombocytopenic purpura and haemolytic anemia)
- Can present late sequelae in individuals asymptomatic at birth (hearing defects and reduced
intelligence).
 Cytomegalovirus (CMV, HHV-5)
Clinical Significance
- Perinatal infection: usually asymptomatic, acquired mainly through infected genital
secretions, and is thought to be 10 times more common than congenital infection.

- Postnatal infection: usually asymptomatic, acquired from breast milk or saliva.

However, in a minority of cases, infectious mononucleosis- like syndrome may develop.
Overall, 2 - 10% of infants are infected by the age of 6 months, worldwide.

- Immunocompromised patients, such as transplant recipients and AIDS patients, are

prone to severe CMV disease (whether primary, reactivation, or re-infection) with
pneumonitis, retinitis, intractable colitis, hepatitis, and encephalopathy.

- In immunocompetent adults, primary CMV can cause mononucleosis-like symptoms,

but with no heterophilic Abs. Reactivation or re-infection with CMV is usually
asymptomatic.
 Cytomegalovirus (CMV, HHV-5)
Laboratory Diagnosis
- Biopsy specimens may be examined histologically for CMV inclusion bodies (“Owl’s
eye”) or for the presence of CMV antigens. However, the sensitivity may be low.

- The pp65 CMV antigenaemia test is now routinely used for

the rapid diagnosis of CMV infection. PCR for the detection
of CMV-DNA is used in some centers.
Treatment
- Congenital infections: the mother should be told of the chances of her baby developing
cytomegalic inclusion disease and perhaps be offered the choice of an abortion.
- Perinatal and postnatal infection: usually not necessary to treat such patients.
- Immunocompromised patients: Anti-CMV agents in current use are Ganciclovir (acyclic
2-deoxyguanosine analogue given i.v.), valganciclovir (L-valyl ester of ganciclovir given
orally), Forscarnet and Cidofovir (nucleotide analogue phosphorylated by cTK given i.v.).
- Transplant patients can also be treated by infusion of anti-CMV CD8 clones derived in
ex-vivo culture.
-Fomivirsen (21-mer anti-sense of the immediate early region of the CMV mRNA) is
given intravitreally (into the vitreous cavity) for the treatment of CMV-induced
retinitis in HIV-infected patients unresponsive to ganciclovir or foscarnet.
 Cytomegalovirus (CMV, HHV-5)
Vaccine
- No licensed vaccine is available.

Prevention
- Prevention of CMV disease in transplant recipients is a very complicated subject
and varies from center to center. It may include the following measures:
i- Screening and matching the CMV status of the donor and recipient.
ii- Use of CMV negative-blood for transfusions.
iii- Administration of CMV immunoglobulin (Cytogam) to seronegative
recipients before and up to 16 weeks after transplant.
iv- Prophylactic administration of antiviral agents such as Ganciclovir (i.v.)
or Valganciclovir (oral).
 Human Herpesviruses 6 and 7 (HHV-6 and HHV-7)
Transmission/Epidemiology
- HHV-6 and HHV-7 are ubiquitous pathogens worldwide, are transmitted mainly
through close contact (respiratory route and saliva) and through breast feeding.
Infections occur rapidly after the age of 4 months, as the effect of maternal antibody
wears off. In adulthood, 90-99% of the population would have been infected by both
viruses

Pathogenesis
- The main target cell is the T-lymphocyte (CD4), although B-lymphocytes may also
be infected. Like other herpesviruses, HHV-6 and HHV-7 remain latent in the body
after primary infection and may reactivate occasionally.
• HHV-6 strains are divided into 2 variants, A and B, with different biological,
molecular and epidemiological properties. No disease has been associated with
HHV-6A. A Direct link of HHV-7 to disease has only been found in few cases.
 Human Herpesviruses 6 and 7 (HHV-6 and HHV-7)
Clinical Significance
- Primary HHV-6B infection (and rarely HHV7) is associated with “Roseola Infantum” also
known as exanthem subitum or sixth disease) which is a classical disease of infants
between the ages of 4 months and two years.

- A spiking fever develops over a period of 2-3 days followed by a mild, red, non-itchy rash
(lacy body rash). The fever can be high enough to cause febrile convulsions and it may be
followed by encephalitis.

- If primary infection or reactivation occurs in adulthood, there is a chance that an IM-like

disease could develop in a similar manner to EBV and CMV.
Laboratory Diagnosis
- Diagnosis is usually made on clinical grounds and serology is the
mainstay of laboratory diagnosis
Treatment
- No treatment is indicated. In certain cases, the use of anti-CMV
drugs has shown some success
Vaccine
- No vaccine is available
 Human Herpesvirus 8 (HHV-8 )
General Characteristics
- Also known as Kaposi sarcoma-associated herpesvirus (KHSV)
- Originally isolated from cells of Kaposi’s sarcoma (KS), the most common cancer in
AIDS patients. HHV-8 DNA is found in almost 100% of cases of KS and the virus is now
firmly associated with KS and with less frequent malignancies such as Castleman’s Disease
and primary effusion lymphomas (due to HHV-8 infection of B cells)

Transmission/Epidemiology
- Unlike other herpesviruses, HHV-8 does not have a ubiquitous distribution. Transmission
is mainly through sexual contact, transplantation, and vertical transmission (rarely). The
seroprevalance of HHV-8 is variable among the general population (3% in USA and 50% in
East Africa) but always high in subgroups, such as homosexuals.

Pathogenesis
- HHV-8 can infect DCs, monocytes, B cells, epithelial cells and fibroblasts
- HHV-8 has a lytic (short period) and a latent (most of the time) phase
- HHV-8 has several oncogenes that play a role in development of Kaposis’s sarcoma
 Human Herpesvirus 8 (HHV-8)
Clinical Significance
- KS is a systemic disease with cutaneous manifestations, a malignancy of lymphatic
endothelium that forms vascular channels filled with blood. Lesions are dark purple and
appear at multiple sites such as skin, oral cavity

Kaposi’s
Sarcoma
Human Herpesvirus 8 (HHV-8)

Kaposi’s Sarcoma
 Human Herpesvirus 8 (HHV-8)
Laboratory Diagnosis
- Some serological test might be helpful
- Detection of HHV-8 DNA in biopsies.
- Virus is not grown in culture.

Treatment
- Involves surgical excision, cryotherapy of lesions, radiation, vinblastine,
Doxorubicin, IFN-alpha, Imiquimod and Alitretinoin gel (Retinoid) for skin lesions.

Vaccine
- At present, no vaccine is available against HHV-8
Infections Caused by Herpesviruses
Summary Table