HERPESVIRUSES
Properties of herpesviruses
? Enveloped double stranded DNA viruses,
? Genome consisits 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
? Size,180-200nm
? Replication,Nuclear,
? Assembly,Nuclear,
? Envelope,Present; associated glycoproteins,
? Tegument,Protein-filled region between capsid
and envelope,
? Capsid,Icosahedral,95-105nm diameter; 162
hexagonal capsomers,
? Core,DNA around protein,~75nm
? Genome,Linear,d/s DNA,105-235kbp
? Common Antigens:None
? Herpes viruses can replicate in human diploid
cells except of BBV
? Produce cytopathic effect(CPE)
? Intranuclear acidophilic inclusion bodies
Categories of herpes virus
正式命名 常用名 病毒亚科 重要生物学性状 所致疾病
人类疱疹病毒 1型
（ HHV-1）
单纯疱疹病毒 1型
（ HSV-1）
? 繁殖快、杀细胞性感染
感觉神经节中潜伏
唇疱疹、龈口炎、角膜结膜炎、
脑炎等
人类疱疹病毒 2型
（ HHV-2）
单纯疱疹病毒 2型
（ HSV-2）
? 同上 生殖器疱疹、新生儿疱疹
人类疱疹病毒 3型
（ HHV-3）
水痘 -带状疱疹病毒
（ VZV）
? 同上 水痘、带状疱疹、脑炎
人类疱疹病毒 4型
（ HHV-4）
Epstein-Barr病毒
（ EBV）
? 淋巴细胞中繁殖与潜伏 传染性单核细胞增多症、
Burkitt淋巴瘤,鼻咽癌（?）
等
人类疱疹病毒 5型
（ HHV-5）
人类巨细胞病毒 ? 常在淋巴细胞、肾脏及
分泌腺体中潜伏
先天性巨细胞包涵体病、单核细
胞增多症、间质性肺炎、先
天性畸形、肝炎
人类疱疹病毒 6型
（ HHV-6）
人类疱疹病毒 6型 ? 同 人巨细胞病毒 婴儿急疹、间质性肺炎、骨髓抑
制
人类疱疹病毒 7型
（ HHV-7）
人类疱疹病毒 7型 ? 同 人巨细胞病毒 未明确
人类疱疹病毒 8型
（ HHV-8）
人类疱疹病毒 8型 ? 同 EB病毒 Kaposi肉瘤
弥猴疱疹病毒 1 猿猴 B病毒 ? 同 HSV 脊髓炎、出血性脑炎
1 Herpes Simplex
Viruses
Properties
? Belong to the alphaherpesvirus subfamily of
herpesviruses
? ds 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 ie,
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)
? Generally HSV-1 causes infection above the belt and
HSV-2 below the belt,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,
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,
? Reactivation - It is well known that many triggers can
provoke a recurrence,These include physical or
psychological stress,infection; especially pneumococcal
and meningococcal,fever,irradiation; including sunlight,
and menstruation,
Pathogenesis
Clinical Manifestations
HSV is involved in a variety of clinical manifestations
which includes ;-
1,Acute gingivostomatitis龈口炎
2,Herpes Labialis (cold sore)唇疱疹
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,
? 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,red ness appears followed by papules and
then vesicles,
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虹膜睫状体炎,chorioretinitis脉络膜视
网膜炎 and cataract白内障
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,
? 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
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,
? It is of utmost importance to make a diagnosis of HSE early,It
is general practice that IV acyclovir is given in all cases of
suspected HSE before laboratory results are available,
Neonatal Herpes Simplex (1)
? Incidence of neonatal HSV infection varies inexplicably from country
to country e.g,from 1 in 4000 live births in the U.S,to 1 in 10000 live
births in the UK
? 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,
? 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,The
widespread vesicular resembles that of chickenpox,
Many organs other than the skin may be involved e.g,
liver,spleen,lungs,and CNS,
? 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
culture,Note the ballooning of
cells,(Linda Stannard,University
of Cape Town,S.A.)
Positive immunofluorescence test for
HSV antigen in epithelial cell,
(Virology Laboratory,New-Yale Haven
Hospital)
Management
At present,there are only a few indications of antiviral chemo therapy,
with the high cost of antiviral drugs being a main consideration,Generally,
antiviral chemotherapy is indicated where the primary infection is
especially severe,where there is dissemination,where sight is threatened,
and herpes simplex encephalitis,
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
2 Varicella- Zoster Virus
Properties
? Belong to the alphaherpesvirus subfamily of
herpesviruses
? ds 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 varicellaform
rash in the distribution of a dermatome,
Pathogenesis
shingles
Varicella
? Primary infection results in varicella (chicken-pox)
? Incubation period of 14-21 days
? Presents fever,lymphadadenopathy,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
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
? 90% of pregnant women already immune,therefore
primary infection is rare during pregnancy,
? 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,
? Zoster immunoglobulin should be given to
susceptible pregnant women who had
contact with suspected cases of varicella,
Laboratory Diagnosis
The clinical presentations of varicella or zoster are so
characteristic that laboratory confirmation is rarely
required,Laboratory diagnosis is required only for
atypical presentations,particularly in the
immunocompromised,
– 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 in cell culture,Note the ballooning of cells,(Coutesy of
Linda Stannard,University of Cape Town,S.A.)
Cytopathic Effect of VZV
Management
? Uncomplicated varicella is a self limited disease and requires no
specific treatment,However,acyclovir had been shown to
accelerate the resolution of the disease and is prescribed by some
doctors,
? 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,HNIG should be given instead,
? 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,
3 Cytomegalovirus
Properties
? Belong to the betaherpesvirus subfamily of
herpesviruses
? ds 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
? CMV is one of the most successful human pathogens,it can be
transmitted vertically or horizontally usually with little effect on the host,
? 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
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
Incidence of Cytomegalic
Disease
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
DEAFF test for CMV
Specimens for Laboratory Diagnosis
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,
4 Epstein-Barr Virus
Pathogenesis
? Transformation of B cells
? Burkitt's lymphoma
? Nasopharyngeal cancer
? Oral hairy leukoplakia
? Infectious mononucleosis
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
but only a few have been identified,
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(IM)
2,Burkitt's lymphoma( BL)
3,Nasopharyngeal carcinoma( NPC)
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,
? 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
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,
Burkitt's Lymphoma
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,
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,
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,
Roseala Infantum
Kaposi’s Sarcoma
Human herpes virus 6
? Worldwide
? In the saliva of the majority of adults (>90%),
? It infects almost all children by the age of two and the
infection is life-long,Again,it replicates in B and T
lymphocytes,megakaryocytes,etc
? Latent infection in T cells, Infected cells are larger than
normal with inclusions in both cytoplasm and nucleus,
? Cell-mediated immunity is essential in control,although
infection is life-long,and the virus can reactivate in
immune-suppression,
Pathogenesis
? Two forms,HHV-6A and HHV-6B,The latter causes
exanthem subitum,otherwise known as roseola
infantum,
? This a common disease of young children (in the US
>45% of children are seropositive for HHV-6 by two
years of age) and symptoms include fever and
sometimes upper respiratory tract infection and
lymphadenopathy,
? Incubation period, 14 days,
Pathogenesis
? The fever subsides leaving a macropapular rash on the trunk
and neck that last a few days longer,In adults,primary
infection is associated with a mononucleosis,
? Patients with HIV have a higher infection rate than the normal
population,
? HHV-6 has been associated with a number of neurological
disorders,including encephalitis and seizures,
? It has been postulated to play a role in multiple sclerosis and
chronic fatigue immunodeficiency syndrome,
Human herpes virus 7
? This virus binds to the CD4 antigen and
replicates in T4 (CD4+) cells and is found in the
saliva of the majority of the adult population
(>75%),
? Most people acquire the infection as children
and it remains with them for the rest of their lives,
It is similar to HHV-6 and may be responsible for
some cases of exanthem subitum
Human herpes virus 8
? This was formerly known as Kaposi`s sarcoma
associated herpes virus and is found in the
saliva of many AIDS patients,
? It infects peripheral blood lymphocytes,
? The distribution of the virus may explain why
some populations of HIV-infected people go
down with Kaposi`s sarcoma
