Herpesviruses

Year III
Properties of herpesviruses
• Enveloped double stranded DNA viruses.
• Genome consists of long and short fragments which may be orientated in
either direction, giving a total of 4 isomers.
• Three subfamilies:
• Alphaherpesviruses - HSV-1, HSV-2, VZV

• Betaherpesviruses - CMV, HHV-6, HHV-7

• Gammaherpesviruses - EBV, HHV-8

• Set up latent or persistent infection following primary infection
• Reactivation are more likely to take place during periods of
immunosuppression
• Both primary infection and reactivation are likely to be more serious in
immunocompromised patients.
Herpesvirus Particle

HSV-2 virus particle. Note that all

herpesviruses have identical
morphology and cannot be
distinguished from each other
under electron microscopy.

(Linda Stannard, University of Cape Town, S.A.)

Herpes Simplex Viruses
Properties
• Belong to the alphaherpesvirus subfamily of herpesviruses

• Double stranded DNA enveloped virus with a genome of

around 150 kb

• The genome of HSV-1 and HSV-2 share 50 - 70% homology.

• They also share several cross-reactive epitopes with each

other. There is also antigenic cross-reaction with VZV.

• Man is the only natural host for HSV.

Epidemiology (1)
• HSV is spread by contact, as the virus is shed in saliva, tears, genital
and other secretions.

• By far the most common form of infection results from a kiss given
to a child or adult from a person shedding the virus.

• Primary infection is usually trivial or subclinical in most individuals.

It is a disease mainly of very young children i.e. those below 5 years.

• There are 2 peaks of incidence, the first at 0 - 5 years and the second
in the late teens, when sexual activity commences.

• About 10% of the population acquires HSV infection through the

genital route and the risk is concentrated in young adulthood.
Epidemiology (2)
• In fact, 40% of clinical isolates from genital sores are HSV-
1, and 5% of strains isolated from the facial area are HSV-2
(This data is complicated by oral sexual practices).

• Following primary infection, 45% of orally infected

individuals and 60% of patients with genital herpes will
experience recurrences.

• The actual frequency of recurrences varies widely between

individuals. The mean number of episodes per year is about
1.6.
Pathogenesis
• During the primary infection, HSV spreads locally and a short-
lived viraemia occurs, whereby the virus is disseminated in the
body. Spread to the to craniospinal ganglia occurs.

• The virus then establishes latency in the craniospinal ganglia.

• The exact mechanism of latency is not known, it may be true

latency where there is no viral replication or viral persistence
where there is a low level of viral replication.
Clinical Manifestations
HSV is involved in a variety of clinical manifestations
which includes ;-
1. Acute gingivostomatitis
2. Herpes Labialis (cold sore)
3. Ocular Herpes
4. Herpes Genitalis
5. Other forms of cutaneous herpes
7. Meningitis
8. Encephalitis
9. Neonatal herpes
 Oral-facial Herpes
• Acute Gingivostomatitis
• Acute gingivostomatitis is the commonest manifestation of
primary herpetic infection.

• The patient experiences pain and bleeding of the gums. 1 - 8

mm ulcers with necrotic bases are present.

• Neck glands are commonly enlarged accompanied by fever.

• Usually a self limiting disease which lasts around 13 days.

Oral-facial Herpes
• Herpes labialis (cold sore)
• Following primary infection, 45% of orally infected individuals will
experience reactivation.
• The actual frequency of recurrences varies widely between individuals.
• Herpes labialis (cold sore) is a recurrence of oral HSV.
• A prodrome of tingling, warmth or itching at the site usually heralds
the recurrence.
• About 12 hours later, redness appears followed by papules and then
vesicles.
Gingivostomatitis
Ocular Herpes
HSV causes a broad spectrum of ocular disease, ranging
from mild superficial lesions involving the external eye, to
severe sight-threatening diseases of the inner eye. Diseases
caused include the following:-

• Primary HSV keratitis – dendritic ulcers

• Recurrent HSV keratitis

• HSV conjunctivitis

• Iridocyclitis, chorioretinitis and cataract

Genital Herpes
• Genital lesions may be primary, recurrent or initial.

• Many sites can be involved which includes the penis, vagina,

cervix, anus, vulva, bladder, the sacral nerve routes, the
spinal and the meninges.

• The lesions of genital herpes are particularly prone to

secondary bacterial infection eg. S.aureus, Streptococcus,
Trichomonas and Candida Albicans.
Genital Herpes
• Dysuria is a common complaint, in severe cases, there may
be urinary retention.

• Local sensory nerves may be involved leading to the

development of a radiculitis.

• A mild meningitis may be present.

• 60% of patients with genital herpes will experience

recurrences. Recurrent lesions in the perianal area tend to be
more numerous and persists longer than their oral HSV-1
counterparts.
Herpes Simplex Encephalitis
• Herpes Simplex encephalitis is one of the most serious
complications of herpes simplex disease.

• There are two forms:

• Neonatal – there is global involvement and the brain is almost
liquefied. The mortality rate approaches 100%.

• Focal disease – the temporal lobe is most commonly affected. This

form of the disease appears in children and adults. It is possible that
many of these cases arise from reactivation of virus. The mortality
rate is high (70%) without treatment.
Neonatal Herpes Simplex (1)
• The baby is usually infected perinatally during passage through the birth
canal.

• Premature rupturing of the membranes is a well recognized risk factor.

• The risk of perinatal transmission is greatest when there is a florid

primary infection in the mother.

• There is an appreciably smaller risk from recurrent lesions in the mother,

probably because of the lower viral load and the presence of specific
antibody

• The baby may also be infected from other sources such as oral lesions
from the mother or a herpetic whitlow in a nurse.
Neonatal Herpes Simplex (2)
• The spectrum of neonatal HSV infection varies from a mild
disease localized to the skin to a fatal disseminated infection.

• Infection is particularly dangerous in premature infants.

• Where dissemination occurs, the organs most commonly

involved are the liver, adrenals and the brain.

• Where the brain is involved, the prognosis is particularly

severe. The encephalitis is global and of such severity that
the brain may be liquefied.
Neonatal Herpes Simplex (3)
• A large proportion of survivors of neonatal HSV
infection have residual disabilities.

• Acyclovir should be promptly given in all suspected

cases of neonatal HSV infection.

• The only means of prevention is to offer caesarean

section to mothers with florid genital HSV lesions.
Other Manifestations
• Disseminated herpes simplex are much more likely to occur in
immunocompromised individuals. Other cutaneous manifestations
include:

• eczema herpeticum which is potentially a serious disease that occurs in

patients with eczema.

• Herpetic whitlow which arise from implantation of the virus into the skin
and typically affect the fingers.

• “zosteriform herpes simplex". This is a rare presentation of herpes

simplex where HSV lesions appear in a dermatomal distribution similar
to herpes zoster.
Laboratory Diagnosis
• Direct Detection
• Electron microscopy of vesicle fluid - rapid result but cannot distinguish
between HSV and VZV
• Immunofluorescence of skin scrappings - can distinguish between HSV and
VZV
• PCR - now used routinely for the diagnosis of herpes simple encephalitis

• Virus Isolation
• HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes
only 1 - 5 days for a result to be available.

• Serology
• Not that useful in the acute phase because it takes 1-2 weeks for before
antibodies appear after infection. Used to document to recent infection.
Cytopathic Effect of HSV in cell Positive immunofluorescence test for
culture: Note the ballooning of HSV antigen in epithelial cell.
cells. (Linda Stannard, University (Virology Laboratory, New-Yale Haven
of Cape Town, S.A.) Hospital)
Management
Acyclovir – this the drug of choice for most situations at present. It is
available in a number of formulations:-
• I.V. (HSV infection in normal and immunocompromised patients)

• Oral (treatment and long term suppression of mucocutaneous herpes and prophylaxis
of HSV in immunocompromised patients)

• Cream (HSV infection of the skin and mucous membranes)

Ophthalmic ointment Famciclovir and valacyclovir – oral only, more

expensive than acyclovir.
Other older agents – e.g. idoxuridine, trifluorothymidine, Vidarabine
(ara-A).
These agents are highly toxic and is suitable for topical use for opthalmic infection only
Varicella- Zoster Virus
Properties
• Belong to the alphaherpesvirus subfamily of
herpesviruses

• Double stranded DNA enveloped virus

• Genome size 125 kbp, long and short fragments

with a total of 4 isometric forms.

• One antigenic serotype only, although there is

some cross reaction with HSV.
Epidemiology
• Primary varicella is an endemic disease. Varicella is one of the
classic diseases of childhood, with the highest prevalence
occurring in the 4 - 10 years old age group.

• Varicella is highly communicable, with an attack rate of 90% in

close contacts.

• Most people become infected before adulthood but 10% of young

adults remain susceptible.

• Herpes zoster, in contrast, occurs sporadically and evenly

throughout the year.
Pathogenesis
• The virus is thought to gain entry via the respiratory tract and
spreads shortly after to the lymphoid system.

• After an incubation period of 14 days, the virus arrives at its main

target organ, the skin.

• Following the primary infection, the virus remains latent in the

cerebral or posterior root ganglia. In 10 - 20% of individuals, a
single recurrent infection occurs after several decades.

• The virus reactivates in the ganglion and tracks down the sensory
nerve to the area of the skin innervated by the nerve, producing a
varicella form rash in the distribution of a dermatome.
Varicella
• Primary infection results in varicella (chickenpox)

• Incubation period of 14-21 days

• Presents fever, lymphadenopathy. a widespread vesicular rash.

• The features are so characteristic that a diagnosis can usually be made on

clinical grounds alone.

• Complications are rare but occurs more frequently and with greater severity
in adults and immunocompromised patients.

• Most common complication is secondary bacterial infection of the vesicles.

• Severe complications which may be life threatening include viral pneumonia,

encephalititis, and haemorrhagic chickenpox.
Rash of Chickenpox
 Herpes Zoster (Shingles)
• Herpes Zoster mainly affect a single dermatome of the skin.
• It may occur at any age but the vast majority of patients are more than 50
years of age.
• The latent virus reactivates in a sensory ganglion and tracks down the
sensory nerve to the appropriate segment.
• There is a characteristic eruption of vesicles in the dermatome which is often
accompanied by intensive pain which may last for months (postherpetic
neuralgia)
• Herpes zoster affecting the eye and face may pose great problems.
• As with varicella, herpes zoster in a far greater problem in
immunocompromised patients in whom the reactivation occurs earlier in life
and multiple attacks occur as well as complications.
• Complications are rare and include encephalitis and disseminated herpes
zoster.
Shingles
Congenital VZV Infection
• Primary infection during pregnancy carries a greater risk of severe
disease, in particular pneumonia.
First 20 weeks of Pregnancy
• Up to 3% chance of transmission to the fetus, recognised congenital
varicella syndrome;
• Scarring of skin

• Hypoplasia of limbs

• CNS and eye defects

• Death in infancy normal

Neonatal Varicella

• VZV can cross the placenta in the late stages of pregnancy

to infect the fetus congenitally.

• Neonatal varicella may vary from a mild disease to a fatal

disseminated infection.

• If rash in mother occurs more than 1 week before delivery,

then sufficient immunity would have been transferred to the
fetus.
Neonatal Varicella

• Zoster immunoglobulin should be given to susceptible

pregnant women who had contact with suspected cases of
varicella.

• Zoster immunoglobulin should also be given to infants

whose mothers develop varicella during the last 7 days of
pregnancy or the first 14 days after delivery.
Laboratory Diagnosis
• Virus Isolation - rarely carried out as it requires 2-3 weeks for a
results.

• Direct detection - electron microscopy may be used for vesicle fluids

but cannot distinguish between HSV and VZV.

• Immunofluorescense on skin scrappings can distinguish between the

two.

• Serology - the presence of VZV IgG is indicative of past infection

and immunity. The presence of IgM is indicative of recent primary
infection.
 Cytopathic Effect of VZV

Cytopathic Effect of VZV in cell culture: Note the ballooning of cells. (Coutesy of
Linda Stannard, University of Cape Town, S.A.)
Management
• Acyclovir should be given promptly immunocompromised individuals with
varicella infection and normal individuals with serious complications such as
pneumonia and encephalitis.

• Herpes zoster in a healthy individual is not normally a cause for concern. The
main problem is the management of the postherpetic neuralgia.

• The International Herpes Management Forum recommends that antiviral therapy

should be offered routinely to all patients over 50 years of age presenting with
herpes zoster.

• Three drugs can be used for the treatment of herpes zoster: acyclovir,
valicyclovir, and famciclovir. There appears to be little difference in efficacy
between them.
Prevention

• Preventive measures should be considered for individuals at

risk of contracting severe varicella infection e.g. leukaemic
children, neonates, and pregnant women

• Where urgent protection is needed, passive immunization

should be given. Zoster immunoglobulin (ZIG) is the
preparation of choice but it is very expensive.

• Where ZIG is not available.

Prevention
• A live attenuated vaccine is available.

• There had been great reluctance to use it in the past, especially in

immunocompromised individuals since the vaccine virus can
become latent and reactivate later on.

• However, recent data suggests that the vaccine is safe, even in

children with leukaemia provided that they are in remission.

• It is highly debatable whether universal vaccination should be

offered since chickenpox and shingles are normally mild diseases.
Cytomegalovirus
Properties
• Belong to the betaherpesvirus subfamily of herpesviruses

• Double stranded DNA enveloped virus

• Nucleocapsid 105nm in diameter, 162 capsomers

• The structure of the genome of CMV is similar to other

herpesviruses, consisting of long and short segments
which may be orientated in either direction, giving a total
of 4 isomers.

• A large no. of proteins are encoded for, the precise

number is unknown.
Epidemiology
• Transmission may occur in utero, perinatally or postnatally. Once infected,
the person carries the virus for life which may be activated from time to
time, during which infectious virions appear in the urine and the saliva.

• Reactivation can also lead to vertical transmission. It is also possible for

people who have experienced primary infection to be reinfected with
another or the same strain of CMV, this reinfection does not differ clinically
from reactivation.

• In developed countries with a high standard of hygiene, 40% of adolescents

are infected and ultimately 70% of the population is infected. In developing
countries, over 90% of people are ultimately infected.
Pathogenesis
• Once infected, the virus remains in the person for life and my be reactivated
from time to time, especially in immunocompromised individuals.

• The virus may be transmitted in utero, perinatally, or postnatally. Perinatal

transmission occurs.

• Perinatal infection is acquired mainly through infected genital secretions, or

breast milk. Overall, 2 - 10% of infants are infected by the age of 6 months
worldwide. Perinatal infection is thought to be 10 times more common than
congenital infection.

• Postnatal infection mainly occurs through saliva. Sexual transmission may

occur as well as through blood and blood products and transplanted organ.
Clinical Manifestations
• Congenital infection - may result in cytomegalic inclusion disease

• Perinatal infection - usually asymptomatic

• Postnatal infection - usually asymptomatic. However, in a minority of cases,

the syndrome of infectious mononucleosis may develop which consists of
fever, lymphadenopathy, and splenomegaly. The heterophil antibody test is
negative although atypical lymphocytes may be found in the blood.

• Immunocompromised patients such as transplant recipients and AIDS

patients are prone to severe CMV disease such as pneumonitis, retinitis,
colitis, and encephalopathy.

• Reactivation or reinfection with CMV is usually asymptomatic except in

immunocompromised patients.
Congenital Infection
• Defined as the isolation of CMV from the saliva or urine within 3 weeks
of birth.

• Commonest congenital viral infection, affects 0.3 - 1% of all live births.

The second most common cause of mental handicap after Down's
syndrome and is responsible for more cases of congenital damage than
rubella.

• Transmission to the fetus may occur following primary or recurrent

CMV infection. 40% chance of transmission to the fetus following a
primary infection.

• May be transmitted to the fetus during all stages of pregnancy.

• No evidence of teratogenecity, damage to the fetus results from

destruction of target cells once they are formed.
Cytomegalic Inclusion Disease
• CNS abnormalities - microcephaly, mental retardation, spasticity,
epilepsy, periventricular calcification.

• Eye - choroidoretinitis and optic atrophy

• Ear - sensorineural deafness

• Liver - hepatosplenomegaly and jaundice which is due to hepatitis.

• Lung - pneumonitis

• Heart - myocarditis

• Thrombocytopenic purpura, Haemolytic anaemia

• Late sequelae in individuals asymptomatic at birth - hearing defects

and reduced intelligence.
Incidence of Cytomegalic Disease

U.S.A. U.K.

No. of live births p.a. 3,000,000 700,000

Rate of congenital CMV 1% 0.3%

No. of infected infants 30,000 2100

Symptomatic at birth (5 - 10% ) 1,500-3,000 105

Fatal disease (~ 20% ) 300-600 22

No. with sequelae (90% of survivors) 1080-2160 83

Asymptomatic (90 - 95% ) 27000 1995

No. with late sequelae 1350-4550 315

 Laboratory Diagnosis (1)
• Direct detection

• biopsy specimens may be examined histologically for CMV

inclusion antibodies 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 in immunocompromised
patients.

• PCR for CMV-DNA is used in some centers but there may be

problems with interpretation.
CMV pp65 antigenaemia test

(Virology Laboratory, New-Yale Haven Hospital)

Laboratory Diagnosis (2)
• Virus Isolation
• conventional cell culture is regarded as gold standard but
requires up to 4 weeks for result.
• More useful are rapid culture methods such as the DEAFF test
which can provide a result in 24-48 hours.
• Serology
• the presence of CMV IgG antibody indicates past infection.
• The detection of IgM is indicative of primary infection
although it may also be found in immunocompromised
patients with reactivation.
Cytopathic Effect of CMV

(Courtesy of Linda Stannard, University of Cape Town, S.A.)

DEAFF test for CMV

(Virology Laboratory, New-Yale Haven Hospital)

Specimens for Laboratory Diagnosis

Site for virus culture Serology

Urine Saliva Blood Tissue affected IgG IgM

Neonates + + - - - +

Adults + - + - + +

Pregnant women - - - - + +

Immunocompromised + + + + + -
Treatment
• Congenital infections - it is not usually possible to detect
congenital infection unless the mother has symptoms of primary
infection. If so, then the mother should be told of the chances of
her baby having cytomegalic inclusion disease and perhaps
offered the choice of an abortion.
• Perinatal and postnatal infection - it is usually not necessary to
treat such patients.
• Immunocompromised patients - it is necessary to make a
diagnosis of CMV infection early and give prompt antiviral
therapy. Anti-CMV agents in current use are ganciclovir,
forscarnet, and cidofovir.
Prevention
• No licensed vaccine is available. There is a candidate live attenuated
vaccine known as the Towne strain but there are concerns about
administering a live vaccine which could become latent and reactivates.
• Prevention of CMV disease in transplant recipients is a very complicated
subject and varies from center to center. It may include the following
measures.
• Screening and matching the CMV status of the donor and recipient
• Use of CMV negative blood for transfusions
• Administration of CMV immunoglobulin to seronegative recipients
prior to transplant
• Give antiviral agents such as acyclovir and ganciclovir
prophylactically.
Epstein-Barr Virus
Epstein-Barr Virus (EBV)
• Belong to the gammaherpesvirus subfamily of herpesviruses
• Nucleocapsid 100 nm in diameter, with 162 capsomers
• Membrane is derived by budding of immature particles
through cell membrane and is required for infectivity.
• Genome is a linear double stranded DNA molecule with 172
kbp
• The viral genome does not normally integrate into the
cellular DNA but forms circular episomes which reside in
the nucleus.
• The genome is large enough to code for 100 - 200 proteins
Epidemiology
• Two epidemiological patterns are seen with EBV.

• In developed countries, 2 peaks of infection are seen : the first in

very young preschool children aged 1 - 6 and the second in
adolescents and young adults aged 14 - 20 Eventually 80-90% of
adults are infected.

• In developing countries, infection occurs at a much earlier age so

that by the age of two, 90% of children are seropositive.

• The virus is transmitted by contact with saliva, in particularly

through kissing.
Pathogenesis
• Once infected, a lifelong carrier state develops whereby a low
grade infection is kept in check by the immune defenses.

• Low grade virus replication and shedding can be demonstrated in

the epithelial cells of the pharynx of all seropositive individuals.

• EBV is able to immortalize B-lymphocytes in vitro and in vivo

• Furthermore a few EBV-immortalized B-cells can be

demonstrated in the circulation which are continually cleared by
immune surveillance mechanisms.

• EBV is associated with several very different diseases where it

may act directly or one of several co-factors.
Disease Association
1. Infectious Mononucleosis
2. Burkitt's lymphoma
3. Nasopharyngeal carcinoma
4. Lymphoproliferative disease and lymphoma in the
immunosuppressed.
5. X-linked lymphoproliferative syndrome
6. Chronic infectious mononucleosis
7. Oral leukoplakia in AIDS patients
8. Chronic interstitial pneumonitis in AIDS patients.
Infectious Mononuclosis

• Primary EBV infection is usually subclinical in childhood.

However in adolescents and adults, there is a 50% chance
that the syndrome of infectious mononucleosis (IM) will
develop.

• IM is usually a self-limited disease which consists of fever,

lymphadenopathy and splenomegaly.

• In some patients jaundice may be seen which is due to

hepatitis. Atypical lymphocytes are present in the blood.
Infectious Mononuclosis
• Complications occur rarely but may be serious e.g. splenic
rupture, meningoencephalitis, and pharyngeal obstruction.

• In some patients, chronic IM may occur where eventually the

patient dies of lymphoproliferative disease or lymphoma.

• Diagnosis of IM is usually made by the heterophil antibody

test and/or detection of EBV IgM.

• There is no specific treatment.

 Burkitt’s Lymphoma (1)
• Burkitt's lymphoma (BL) occurs endemically in parts of Africa
(where it is the commonest childhood tumour) and Papua New
Guinea. It usually occurs in children aged 3-14 years. It respond
favorably to chemotherapy.

• It is restricted to areas with holoendemic malaria. Therefore it

appears that malaria infection is a cofactor.

• Multiple copies of EBV genome and some EBV antigens can be

found in BL cells and patients with BL have high titres of
antibodies against various EBV antigens.
Burkitt’s Lymphoma (2)
• BL cells show a reciprocal translocation between the long arm of
chromosome 8 and chromosomes 14, 2 or 22.

• This translocation result in the c-myc oncogene being transferred to

the Immunoglobulin gene regions. This results in the deregulation of
the c-myc gene. It is thought that this translocation is probably
already present by the time of EBV infection and is not caused by
EBV.

• Sporadic cases of BL occur, especially in AIDS patients which may or

may not be associated with EBV.

• In theory BL can be controlled by the eradication of malaria (as has

happened in Papua New Guinea) or vaccination against EBV.
Nasopharyngeal Carcinoma
• Nasopharyngeal carcinoma (NPC) is a malignant tumour of the
squamous epithelium of the nasopharynx. It is very prevalent in S. China,
where it is the commonest tumour in men and the second commonest in
women.
• The tumour is rare in most parts of the world, though pockets occur in N.
and C. Africa, Malaysia, Alaska, and Iceland.
• Multiple copies of EBV genome and EBV EBNA-1 antigen can be
found in cells of undifferentiated NPC. Patients with NPC have high
titres of antibodies against various EBV antigens.
• Besides EBV there appears to be a number of environmental and genetic
cofactors in NPC.
• NPC usually presents late and thus the prognosis is poor.
• In theory NPC can be prevented by vaccination.
 Immunocompromised Patients
• After primary infection, EBV maintains a steady low grade latent infection
in the body. Should the person become immunocompromised, the virus
will reactivate. In a few cases, lymphoproliferative lesions and lymphoma
may develop. These lesions tend to be extranodal and in unusual sites such
as the GI tract or the CNS.

• Transplant recipients e.g. renal - EBV is associated with the development

of lymphoproliferative disease and lymphoma.

• AIDS patients - EBV is associated with oral leukoplakia and with various
Non-Hodgekin’s lymphoma.

• Ducan X-linked lymphoproliferative syndrome - this condition occurs

exclusively in males who had inherited a defective gene in the X-
chromosome . This condition accounts for half of the fatal cases of IM.
Diagnosis
• Acute EBV infection is usually made by the heterophil antibody test and/or
detection of anti-EBV VCA IgM.

• Cases of Burkitt’s lymphoma should be diagnosed by histology. The tumour

can be stained with antibodies to lambda light chains which should reveal a
monoclonal tumour of B-cell origin. In over 90% of cases, the cells express
IgM at the cell surface.

• Cases of NPC should be diagnosed by histology.

• The determination of the titre of anti-EBV VCA IgA in screening for early
lesions of NPC and also for monitoring treatment.

• A patient with with non-specific ENT symptoms who have elevated titres of
EBV IgA should be given a thorough examination.
Vaccination
• A vaccine against EBV which prevents primary EBV infection
should be able to control both BL and NPC.

• Such a vaccine must be given early in life. Such a vaccine would

also be useful in seronegative organ transplant recipients and those
developing severe IM, such as the male offspring of X-linked
proliferative syndrome carriers.

• The vaccine should not preferably be a subunit vaccine since there is

a danger that a live vaccine may still have tumorigenic properties.

• The antigen chosen for vaccine development is the MA antigen gp

340/220 as antibodies against this antigen are virus neutralizing.

• This vaccine is being tried in Africa.

Other Human Herpes Viruses
Properties of HHV-6 and 7
• Belong to the betaherpesvirus subfamily of herpesviruses

• Double stranded DNA genome of 170 kbp

• The main target cell is the T-lymphocyte, although B-

lymphocytes may also be infected.

• HHV-6 and HHV-7 share limited nucleotide homology and

antigenic cross-reactivity.

• It is thought that HHV-6 and HHV-7 are related to each other

in a similar manner to HSV-1 and HSV-2.
Epidemiology and Pathogenesis
• HHV-6 and HHV-7 are ubiquitous and are found worldwide.

• They are transmitted mainly through contact with saliva and

through breast feeding.

• HHV-6 and HHV-7 infection are acquired rapidly after the age of
4 months when the effect of maternal antibody wears off.

• By the time of adulthood, 90-99% of the population had been

infected by both viruses.

• Like other herpesviruses, HHV-6 and HHV-7 remains latent in the

body after primary infection and reactivates from time to time.
 Clinical Manifestations (1)
• Primary HHV-6 infection is associated with Roseala
Infantum, which is a classical disease of childhood.

• Most cases occur in infants between the ages of 4 months

and two years.

• A spiking fever develops over a period of 2 days followed

by a mild rash. The fever is high enough to cause febrile
convulsions.

• There are reports that the disease may be complicated by

encephalitis.
Clinical Manifestations (2)
• If primary infection is delayed until adulthood, there is a small
chance that an infectious mononucleosis-like disease may develop
in a similar manner to EBV and CMV.

• There is no firm evidence linking HHV-6 to lymphomas or

lymphoproliferative diseases.

• There is no firm disease association with HHV-7 at present.

• Although both viruses may be reactivated in immunocompromised

patients, it is yet uncertain whether they cause significant disease
since CMV is almost invariably present.
Roseala Infantum
Diagnosis and Management
• Rosela Infantum has a very characteristic presentation and a
diagnosis can usually be made on clinical grounds alone.

• Therefore very few virology laboratories offer a diagnostic

service for HHV-6 or HHV-7 infection.

• The technique for virus isolation is complicated and thus

not practicable as a routine diagnostic procedure.

• Therefore serology is the mainstay of diagnosis where

specific IgM and IgG are detected.

• There is no specific antiviral treatment for HHV-6 infection.

Human Herpes Virus 8
• Belong to the gammaherpesviruses subfamily of herpesviruses

• Originally isolated from cells of Kaposi’s sarcoma (KS)

• Now appears to be firmly associated with Kaposi’s sarcoma as well as

some lesser known malignancies such as Castleman’s disease and
primary effusion lymphomas

• HHV-8 DNA is found in almost 100% of cases of Kaposi’s sarcoma

• Most patients with KS have antibodies against HHV-8

• The seroprevalence of HHV-8 is low among the general population but

is high in groups of individuals susceptible to KS, such as homosexuals.

• Unlike other herpesviruses, HHV-8 does not have a ubiquitous

distribution.
Kaposi’s Sarcoma