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MICROBIOLOGY Dra. Bunyi 3rd shifting Dec.

5, 2007

Herpesviruses shar, cams, joy Class no.:

 Mean number of episodes per year: 16

 enveloped double stranded DNA viruses PATHOGENESIS:
 genome: long and short fragments oriented in either  Primary infection, HSV spreads locally and a short-
direction, giving a total of 4 isomers lived viremia occurs, whereby the virus is
 set up latent or persistent infection following primary disseminated in the body. Spread to the
infection craniospinal ganglia occurs.
 Reactivation – more likely during periods of  The virus then establishes latency in the
immunosuppression craniospinal ganglia.
 Both primary infection and reactivation are likely to be  The exact mechanism of latency is not known. It
more serious in immunocompromised patients may be true latency where there is no viral
 3 subfamilies: replication or viral persistence where there is a
1. Alphaherpesviruses – HSV-1, HSV-2, VZV; rapid low level of viral replication.
growth, latency in sensory ganglia  Reactivation – triggers can provoke a recurrence.
2. Betaherpesviruses – CMV, HHV-6, HHV-7; slow These include:
growth; restricted host range o Physical or psychological stress
3. Gammaherpesviruses – EBV, HHV-8; growth in o Infection, especially pneumococcal and
lymphoblastoid cells meningococcal
o Fever
HERPESVIRUS PARTICLE o Irradiation, including sunlight
ALL herpesviruses have identical morphology and cannot o Menstruation
be distinguished from each other under electron
HSV is involved in a variety of clinical manifestations
HERPES SIMPLEX VIRUS which includes:
PROPERTIES:  Acute gingivostomatitis
 Belong to the α-herpesvirus subfamily of  Herpes labialis (cold sore)
herpesviruses  Ocular herpes
 Double stranded DNA enveloped virus with a  Herpes genitalis
genome of around 150 kb  Other forms of cutaneous herpes
 The genome of HSV-1 and HSV-2  Meningitis
o Share 50-70% homology  Encephalitis
o Share several cross-reactive epitopes with  Neonatal herpes
each other
o Also antigenic cross-reaction with VZV ACUTE GINGIVOSTOMATITIS
 Man is the only natural host for HSV  Commonest manifestation of primary herpetic
EPIDEMIOLOGY:  Manifestations: pain and bleeding of the gums
 HSV – spread by contact (shed in saliva, tears, o 1-8 mm ulcers with necrotic bases are present
genital and other secretions) o Neck glands are commonly enlarged
 most common form of infection result from a KISS accompanied by fever
given to a child or adult from a person shedding  Usually a self-limiting disease which lasts around
the virus 13 days
 primary infection:
o usually trivial or subclinical in most individuals HERPES LABIALIS (COLD SORE)
o disease mainly of very young children (<5  Following primary infection, 45% of orally infected
years) individuals will experience reactivation
 two peaks of incidence:  Herpes labialis is a recurrence of oral HSV
o 0-5 years  A prodrome of tingling, warmth or itching at the
o Late teens (sexual activity commences) site usually heralds the recurrence. About 12
 10% of the population acquires HSV infection hours later, redness appears followed by papules
through the genital route and the risk is and then vesicles.
concentrated in young adulthood
 Generally: OCULAR HERPES
o HSV-1 causes infection above the belt HSV causes a broad spectrum of ocular disease, ranging
o HSV-2 below the belt from mild superficial lesions involving the external eye to
 Clinical isolates: severe sight-threatening diseases of the inner eye.
o 40% from genital sores are HSV-1 Diseases caused include the following:
o 5% of strains isolated from the facial area are  Primary HSV keratitis – dendritic ulcers
HSV-2 (data is complicated by oral sexual  Recurrent HSV keratitis
practices)  HSV conjunctivitis
 Following the primary infection, 45% of orally  Iridocyclitis, chorioretinitis, and cataract
infected individuals and 60% of patients with
genital herpes will experience recurrences GENITAL HERPES
 Actual frequency of recurrences varies widely  Genital lesions may be primary, recurrent, or
between individuals initial

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 Sites: penis, vagina, cervix, anus, vulva, bladder, o Herpetic whitlow: arise from implantation of
sacral nerve routes, spine and meninges the virus into the skin and typically affect the
o Lesions of genital herpes prone to secondary fingers
bacterial infection o Zosteriform herpes simplex: rare presentation
o E.g., S. aureus, Streptococcus, Trichomonas, of herpes simplex where HSV lesions appear is
C. albicans a dermatomal distribution similar to herpes
 Dysuria: common complaint; in severe cases, zoster
there may be urinary retention
 Local sensory nerves may be involved leads to LABORATORY DIAGNOSIS:
radiculitis  Direct detection:
 A mild meningitis may be present o EM of vesicle fluid: rapid result but cannot
 60% of patients with genital herpes will distinguish between HSV and VZV
experience recurrences. Recurrent lesions in the o IF of skin scrapings: can distinguish between
perianal areas tend to be more numerous and HSV and VZV
persists longer than their oral HSV-1 counterpart. o PCR: diagnosis of herpes simplex encephalitis
 Virus isolation:
HERPES SIMPLEX ENCEPHALITIS o HSV-1 and HSV-2 are among the easiest
 One of the most serious complications of HSV viruses to cultivate; takes only 1-5 days
disease  Serology:
 2 forms: o Not that useful in the acute phase because it
o Neonatal: global involvement; brain is almost takes 1-2 weeks for before antibodies appear
liquefied; mortality rate approaches 100% after infection. Used to document to recent
o Focal disease: temporal lobe most commonly infection.
affected; appears in children and adults; arise
from reactivation of virus; mortality rate is MANAGEMENT:
high (70%) without treatment General indications for antiviral chemotherapy:
 Utmost importance: make a diagnosis of HSE early  Where the primary infection is especially severe
o IV acyclovir: given in all cases of suspected of  Where there is dissemination
HSE before laboratory results are available  Where sight is threatened
 Herpes simplex encephalitis
 Incidence varies from country to country Acyclovir – DOC for most situations at present. Available
o US: 1 in 4000 live births formulations:
o UK: 1 in 10000 live births  IV (HSV infection in normal and
 Baby is usually infected perinatally during immunocompromised patients)
passage through the birth canal  Oral (treatment and long term suppression of
 Premature rupturing of the membranes is a well mucocutaneous herpes and prophylaxis of HSV in
recognized risk factor immunocompromised patients)
 Risk of perinatal transmission: greatest when  Cream )HSV infection of the skin and mucus
there is a florid primary infection in the mother membranes)
 Smaller risk from recurrent lesions in the mother:  Ophthalmic ointment
lower viral load and the presence of specific
antibodies Famiciclovir and Valacyclovir – oral only, more expensive
 Other sources: oral lesions from the mother or a than acyclovir
herpetic whitlow in a nurse
 Spectrum: mild disease; localized to the skin  Other older agents – e.g., idoxuridine, trifluorothymidine,
ftal disseminated infection vidarabine (ara-A)
 Infection: particularly dangerous in premature  These agents are highly toxic and is suitable for
infants topical use for ophthalmic infection only.
 Organs involved in disseminated disease:
o Liver, adrenals and the brain VARICELLA-ZOSTER VIRUS
o Brain involvement: prognosis is severe PROPERTIES:
 Belong to the herpesvirus subfamily of
 Encephalitis is global; brain may be
 Double stranded DNA enveloped virus
 Survivors: residual disabilities
 Genome size is 125 kbp, long and short fragments
 Acyclovir should be promptly given in all
with a total of 4 isometric forms
suspected cases of neonatal HSV infection
 One antigenic serotype only, although there is
 Only means of prevention: offer C-section to
some cross reaction with HSV
mothers with florid genital HSV lesions
 Primary varicella is an endemic disease; classic
 Disseminated herpes simplex: more likely to occur
diseases of childhood
in immunocompromised individuals
o Highest prevalence: 4-10 y/o age group
o Vesicular lesions resembles that of chicken pox
o Involved organs other than skin: liver, spleen,  Varicella is highly communicable, attack rate of
lungs, CNS 90% in close contacts
 Other cutaneous manifestations include:  Most people become infected before adulthood
o Eczema herpeticum: potentially a serious but 10% of young adults remain susceptible
disease that occurs in patients with eczema  Herpes zoster: occurs sporadically and evenly
throughout the year

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 Entry via the respiratory tract and spreads to the  If rash in mother occurs > 1 week before delivery,
lymphoid system sufficient immunity transferred to the fetus
 After an IP of 14 days, the virus arrives at its main  VZIg should be given to susceptible pregnant
target organ, the skin women who had contact wit suspected cases of
 Following the primary infection, the virus remains varicella
latent in the cerebral or posterior root ganglia  VZIg should also be given to infants whose
o In 10-20% of individuals, a single recurrent mothers develop varicella during the last 7 days
infection occurs after several decades of pregnancy or the first 14 days after delivery
 Virus reactivates in the ganglion and tracks down
the sensory nerve to the area of the skin LABORATORY DIAGNOSIS:
innervated by the nerve, producing a varicella  Clinical presentation: characteristic
form rash in the distribution of the dermatome  Laboratory diagnosis: required only for atypical
presentations, particularly in the
VARICELLA immunocompromised
 Primary infection results in varicella (chickenpox) o Virus isolation: rarely carried out; results
 IP of 14-21 days available after 2-3 weeks
 Manifestations: o Direct detection – EM may be used for vesicle
o Fever, lymphadenopathy, a widespread fluids but cannot distinguish between HSV and
vesicular spread VZV
 Clinical features are characteristic o IF on skin scrapings can distinguish between
o Diagnosis made on clinical grounds alone the two
 Complications are rare o Serology: (+) VZV IgG – past infection and
o Occurs more frequently and with greater immunity
severity in adults and immunocompromised (+) IgM – recent primary infection
patients  Culture: cytopathic effect on cells
 Most common complication: secondary bacterial
infection MANAGEMENT:
 Severe complications: life threatening – viral  Uncomplicated varicella: self-limited; no specific
pneumonia, encephalitis, and hemorrhagic treatment
chickenpox o Acyclovir: accelerate the resolution of the
 Herpes zoster mainly affect a single dermatome of  Immunocompromised individuals
the skin  Individuals with serious complicationsL
 May occur at any age; majority of patients are pneumonia and encephalitis
>50 y/o  Herpes zoster in a healthy individual: not a cause
 Latent virus reactivates in a sensory ganglion and for concern
tracks down the sensory nerve to the appropriate o Management of the postherpetic neuralgia can
segment be problematic
 Eruption of vesicles in the dermatome is often o The International Herpes Management Forum
accompanied by intense pain which may last for recommends that antiviral therapy should be
months (postherpetic neuralgia) offered routinely to all patients over 50 y/o
 Herpes zoster affecting the eye and face may presenting with herpes zoster
pose great problems o 3 drugs for the treatment of herpes zoster:
 As with varicella, herpes zoster is a far greater acyclovir, valacyclovir, and famciclovir. There
problem in immunocompromised patients in whom appears to be little difference in efficacy
the reactivation occurs earlier in life and multiple between them
attacks occur as well as complications
 Complications: rare and include encephalitis and PREVENTION:
disseminated herpes zoster  Preventive measures: considered at risk of
contracting severe varicella infection e.g.
CONGENITAL VZV INFECTION: leukemic children, neonates, and pregnant women
 90% of pregnant women already immune,  Where urgent protection is needed, passive
therefore, primary infection is rare during immunization should be given
pregnancy o Varicella zoster immunoglobulin (VZIG) is the
 Primary infection during pregnancy carries a preparation of choice but is very expensive
greater risk of severe disease, in particular, o A live attenuated vaccine is available
pneumonia  Safe, even in children with leukemia
 First 20 weeks of pregnancy: provided that they are in remission
o 3% chance of transmission to the fetus CYTOMEGALOVIRUS
o Recognized congenital varicella syndrome: PROPERTIES:
 Scarring of skin  Belong to the betaherpesvirus subfamily of
 Hypoplasia of limbs herpesviruses
 CNS and eye defects  Double stranded DNA enveloped virus
 Death in infancy normal  Nucleocapsid 150 nm in diameter, 162 capsomers
 Genomic structure of CMV is similar to other
NEONATAL VARICELLA herpesviruses, consisting of long and short
 VZV can cross the placenta in the late stages of segments which may be oriented in either
pregnancy to infect the fetus congenitally direction, giving a total of 4 isomers
 Neonatal varicella: vary from a mild disease to a  A large number of proteins are encoded for, the
fatal disseminated infection precise number is unknown

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EPIDEMIOLOGY:  No evidence of teratogenicity, damage to the
 CMV: one of the most successful human fetus results from destruction of target cells once
pathogens they are formed
o Can be transmitted vertically or horizontally
usually with little effect on the host CYTOMEGALIC INCLUSION DISEASE
 Transmission may occur in utero, perinatally or  CNS abnormalities:
postnatally o Microcephaly, mental retardation, spasticity,
 Once infected, the person carries the virus for life epilepsy, periventricular calcification
which may be activated from time to time, during  Eye: chorioretinitis and optic atrophy
which infectious virions appear in the urine and  Ear: sensorineural deafness
the saliva  Liver: hepatosplenomegaly and jaundice due to
 Reactivation can also lead to vertical transmission hepatitis
 It is also possible for people who have  Lung: pneumonitis
experienced primary infection to be reinfected  Heart: myocarditis
with another or the same strain of CMV, this  Thrombocytopenic purpura, hemolytic anemia
reinfection does not differ clinically from  Late sequelae in individuals asymptomatic at
reactivation birth: hearing defects and reduced intelligence
 In developed countries with a high standard of
hygiene, 40% of adolescents are infected and INCIDENCE OF CYTOMEGALIC DISEASE:
ultimately 70% of the population is infected USA UK
 In developing countries, over 90% of people are No. of live
ultimately infected 3,000,000 700,000
births p.a.
Rate of
Congenital CMV
 Once infected, the virus remains in the person for No. of Infected
life 30,000 2,100
o May be reactivated from time to time, Symptomatic at
especially in immunocompromised individuals 1,500 – 3,000 105
Birth (5-10%)
 Transmission: in utero, perinatally, or postnatally. Fatal Disease
Perinatal transmission occurs 300-600 22
 Perinatal infection: acquired mainly through No. With
infected genital secretions, or breast milk Sequelae (90% 1080-2160 83
o 2-10% of infants infected by the age of 6 of survivors)
months Asymptomatic
o Perinatal infection: 10x more common than 27,000 1,995
congenital infection No. with Late
 Postnatal infection mainly occurs through saliva. 1,350-4,550 315
Sexual transmission may occur as well as through
blood and blood products and transplanted organ. LABORATORY DIAGNOSIS:
 Direct detection:
CLINICAL MANIFESTATIONS: o Biopsy specimens: histologic examination for
 Congenital infection: result in cytomegalic CMV inclusion antibodies or for the presence of
inclusion disease CMV antigens
 Perinatal infection: usually asymptomatic  Sensitivity may be low
 Postnatal infection: usually asymptomatic o The pp65 CMV antigenaemia test: routinely
o Minority of cases: a syndrome of infectious used for rapid diagnosis of CMV infection in
mononucleosis may develop – fever, immunocompromised patients
lymphadenopathy, and splenomegaly. The o PCR for CMV-DNA: used in some centers but
heterophil antibody test (-); atypical there may be problems with interpretation
lymphocytes may be found in the blood  Virus isolation
 Immunocompromised patients: transplant o Conventional cell culture: gold standard
recipients and AIDS patients are prone to severe  Requires up to 4 weeks for result
CMV disease such as pneumonitis, retinitis, colitis, o More useful: rapid culture methods such as the
and encephalopathy DEAFF test – provide a result within 24-48
 Reactivation or reinfection with CMV is usually hours
asymptomatic EXCEPT in immunocompromised  Serology:
patients o (+) CMV IgG antibody: past infection
o (+) CMV IgM antibody: primary infection; also
found in immunocompromised patients with
 Definition: isolation of CMV from the saliva or
urine within 3 weeks of birth
 Most common congenital viral infection; affects SPECIMENS FOR LABORATORY DIAGNOSIS:
0.3-1% of all live births Serolog
 2 nd most common cause of mental handicap after Site for Virus Culture
Down’s syndrome; responsible for more cases of Tissue
congenital damage than rubella Urin Sali Bloo Ig Ig
 Transmission to the fetus may occur following e va d G M
primary or recurrent CMV infection Neonates + + - - - +
o 40% chance of transmission to the fetus Adults + - + - + +
following a primary infection Pregnant
 May be transmitted to the fetus during all stages - - - - + +
of pregnancy
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+ + + + + -
1. Infectious Mononucleosis
TREATMENT: 2. Burkitt’s Lymphoma
 Congenital infections: not usually possible to 3. Nasopharyngeal Carcinoma
detect congenital infection unless the mother has 4. Lymphoproliferative Disease and Lymphoma
symptoms of primary infection. ? chances of her in the Immunosuppressed
baby having CID 5. X-linked Lymphoproliferative Syndrome
o ? offer the choice of an abortion 6. Chronic Infectious Mononucleosis
 Perinatal and postnatal infection: not necessary to 7. Oral Leukoplakia in AIDS Patients
treat such patients 8. Chronic Interstitial Pneumonitis in AIDS
 Immunocompromised patients: early diagnosis of Patients
CMV infection and give prompt antiviral therapy
o Anti-CMV agents in current use are ganciclovir, INFECTIOUS MONONUCLEOSIS:
foscarnet, and cidofovir  Primary EBV infection:
o Usually subclinical in childhood
PREVENTION: o Adolescents and adults: 50% chance that the
 No licensed vaccine available: syndrome of IM will develop
o Concern: administering a live vaccine which  IM: self-limiting disease – fever, lymphadenopathy
can become latent and reactivates and splenomegaly
 Prevention in transplant recipients: very o In some: jaundice (due to hepatitis); (+)
complicated and varies from center to center. It atypical lymphocytes in the blood
may include the following measures:  Complications: rare but may be serious
o Screening and matching the CMV status of the o E.g. splenic rupture, meningoencephalitis,
donor and recipient pharyngeal obstruction
o Use of CMV negative blood for transfusions  Chronic IM may occur where eventually the
o Administration of CMV immunoglobulin to patient dies of lymphoproliferative disease or
seronegative recipients prior to transplant lymphoma
o Give antiviral agents such as acyclovir and  Diagnosis of IM: heterophil antibody test and/or
ganociclovir prophylatically detection of EBV IgM
 NO specific treatment
 Belong to the gammaherpesvirus subfamily  Burkitt’s lymphoma: occurs endemically in parts
 Nucleocapsid: 100 nm in diameter, 162 capsomers of Africa (most common childhood tumor) and
Papua New Guinea
 Membrane is derived by budding of immature
o Usually seen in children age 3-14 years
particles through cell membrane and is required
for infectivity o Responds favorably to chemotherapy
 Genome: linear double stranded DNA; 172 kbp  Restricted to areas with holoendemic malaria.
Therefore it appears that malaria infection is a
 Viral genome does not normally integrate into the
cellular DNA but forms circular epitomes which
reside in the nucleus  Multiple copies of EBV genome and some EBV
antigens can be found in BL cells and patients
 The genome is large enough to code for 100-200
with BL have high titres of antibodies against
proteins but only a few have been identified
various EBV antigens.
EPIDEMIOLOGY:  BL cells show a reciprocal translocation between
the long arm of chromosome 8 and chromosomes
 Two epidemiological patterns seen with EBV
14, 2 or 22
 Developed countries: 2 peaks of infection
 This translocation result in the c-myc oncogene
o Preschool children aged 1-6
being transferred to the immunoglobulin gene
o Adolescents and young adults aged 14-20
regions  results in the deregulation of the c-myc
o Eventually 80-90% of adults are infected
gene. It is thought that this translocation is
 Developing countries: much earlier age so that by probably already present by the time of EBV
the age of 2, 90% of children are seropositive infection and is not caused by EBV.
 Transmitted by contact with saliva (kissing)  Sporadic cases of BL occur, especially in AIDS
patients which may or may not be associated with
 Lifelong carrier stage develops once infected,  In theory, BL can be controlled by the eradication
whereby a low grade infection is kept in check by of malaria (as has happened in Papua New
the immune defenses Guinea) or vaccination against EBV
 Low grade virus replication and shedding:
demonstrated in the epithelial cells of the pharynx NASOPHARYNGEAL CARCINOMA (NPC):
of all seropositive individuals  Malignant tumor of the squamous epithelium of
 EBV: able to immortalize B-lymphocytes in vitro the nasopharync
and in vivo  Prevalent in South China: most common tumor in
 Few EBV-immortalized B-cells can be men and second common in women
demonstrated in the circulation which are  Rare in most parts of the world, though pockets
continually cleared by the immune surveillance occur in North and Central Africa, Malaysia,
mechanisms Alaska, and Iceland
 EBV is associated with several very different  Multiple copies of EBV genome and EBV EBNA-1
diseases where it may act directly or one of antigen can be found in cells of undifferentiated
several co-factors

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NPC. Patients with NPC have high titres of  HHV-6 and HHV-7: ubiquitous, found worldwide
antibodies against various EBV antigens  Transmitted mainly through contact with saliva
 Environmental and genetic cofactors in NPC and through breast feeding
 NPC usally presents late and thus the prognosis is  HHV-6 and HHV-7 infections are acquired rapidly
poor after the age of 4 months when the effect of
 In theory, NPC can be prevented by vaccination maternal antibody wears off
 Adulthood, 90-99% of the population had been
IMMUNOCOMPROMISED PATIENTS: infected by both viruses
 After primary infection, EBV maintains a steady  HHv-6 and HHV-7 remains latent in the body after
low grade latent infection in the body. Should the primary infection and reactivates from time to
person become Immunocompromised, the virus time
will reactivate.
o In some, lymphoproliferative lesions and CLINICAL MANIFESTATIONS:
lymphoma may develop. These lesions tend to  Primary HHV-6 infection: associated with Roseola
be extranodal and in unusual sites such as the infantum
GI tract or the CNS  Infants: 4 months and 2 years
 Transplant recipients: EBV is associated with the  A spiking fever develops over a period of 2 days
development of lymphoproliferative disease and followed by a mild rash. The fever is high enough
lymphoma to cause febrile convulsions.
 AIDS patients: EBV is associated with oral  May be complicated by encephalitis
leukoplakia and with various non-Hodgkin’s  If primary infection is delayed until adulthood,
lymphoma there is a small chance that an IM-like disease
 Ducan X-linked lymphoproliferative syndrome: may develop in a similar manner to EBV and CMV
occurs exclusively in males who had inherited a  NO firm evidence linking HHV-6 to lymphomas or
defective gene in the X chromosome. This lymphoproliferative diseases
condition accounts for half of the datal cases of  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
 Acute EBV Infection: heterophil antibody test is almost invariably present
and/or detection of anti-EBV VCA IgM
 Burkitt’s lymphoma histolohy: tumor can be DIAGNOSIS AND MANAGEMENT:
stained with antibodies to lambda light chains  Roseola infantum: clinical
which reveal a monoclonal tumor of B-cell origin.
 Very few virology laboratories offer a diagnostic
In over 90% of cases, the cells express IgM at the
service for HHV-6 or HHV-7 infection
cell surface
 Virus isolation: complicated
 NPC: histology
 Serology: mainstay of diagnosis – specific IgM and
 The determination of the titre of anti-EBV VCA IgA
IgG are detected
in screening for earl lesions of NPC and also for
 NO specific antiviral treatment
monitoring treatment.
 A patient with non-specific ENT symptoms who
have elevated titres of EBV IgA should be given a
 Belong to the gammaherpesvirus subfamily
thorough examination.
 Originally isolated from cells of Kaposi’s sarcoma
 A vaccine against EBV which prevents primary  Associated wit KS as well as some lesser known
EBV infection should be able to control both BL malignancies such as Castleman’s disease and
and NPC primary effusion lymphomas
 Must be given early in life; also useful in  HHV-8 DNA is found in almost 100% of cases of
seronegative organ transplant recipients and Kaposi’s sarcoma
those developing severe IM, such as the male  Most patients with KS have antibodies against
offspring of X-linked proliferative syndrome HHV-8
carriers  Seroprevalence of HHV-8: low among general
 The antigen chosen for vaccine development is population but is high in groups of individuals
the MA antigen gp 340/220 as antibodies against susceptible to KS, such as homosexual
this antigen are virus neutralizing  Does not have a ubiquitous distribution
 This vaccine is being tried in Africa


 Belong to the betaherpesvirus subfamily of
 Double stranded DNA genome of 170 kbp
 Main target cell: 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-


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