Herpesviruses

Osama khider
 Properties of herpesviruses
 Enveloped double stranded DNA viruses.
 HSV-1, HSV-2, VZV
 - CMV, HHV-6, HHV-7
 - 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.
Herpes Simplex
Viruses
 Properties

 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.
 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)
 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.
 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 sensory nerve ganglia.
 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.
 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
Gingivostomatitis
 Ocular Herpes

 Primary HSV keratitis

 Recurrent HSV keratitis
 HSV conjunctivitis
 Genital Herpes
 Many sites can be involved which includes the penis,
vagina, cervix, anus,, 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.
 Herpes Simplex Encephalitis
 Herpes Simplex encephalitis is one of the most serious complications
of herpes simplex disease. There are two forms:
 Neonatal
 Focal disease
 Neonatal Herpes Simplex
 The baby is usually infected perinatally during passage through the
birth canal.
 The baby may also be infected from other sources such as oral lesions
from the mother
 The spectrum of neonatal HSV infection varies from a mild disease
localized to the skin to a fatal disseminated infection.
 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.
 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..
Cytopathic Effect of HSV in cell Positive immunofluorescence test for
culture: Note the ballooning of HSV antigen in epithelial cell.
cells.
 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.

Prevention : avoid contact

Varicella- Zoster Virus
 Properties
 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.
 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.
 Varicella
 Primary infection results in varicella (chickenpox)
 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.
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.
Shingles
 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

Cytopathic Effect of VZV in cell culture: Note the ballooning of cells.

 Management &Prevention
 Acyclovir should be given promptly immunocompromised individuals with
varicella infection and normal individuals with serious complications such as
pneumonia and encephalitis.
 Three drugs can be used for the treatment of herpes zoster: acyclovir,
valiciclovir, and famciclovir. There appears to be little difference in efficacy
between them.
 Where urgent protection is needed, passive immunization should be given.
Zoster immunoglobulin (ZIG) is the preparation of choice but it is very
expensive.
 A live attenuated vaccine is available.
Cytomegalovirus
 Properties
 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.
 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.
 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.
transmission occurs.
 Perinatal infection is acquired mainly through infected genital
secretions, or breast milk.
 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 - (mental handicap ) may result in cytomegalic
inclusion disease
 Perinatal infection - usually asymptomatic
 Postnatal infection - usually asymptomatic.
 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 I mmunocompromised patients.
 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
 Laboratory Diagnosis (2)
 Virus Isolation
 conventional cell culture is regarded as gold standard but
requires up to 4 weeks for result.
 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
 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..
 Screening and matching the CMV status of the donor and recipient
 Use of CMV negative blood for transfusions
 Give antiviral agents such as acyclovir and ganciclovir
prophylactically.
Epstein-Barr Virus
 Disease Association
1. Infectious Mononucleosis
2. Burkitt's lymphoma
3. Nasopharyngeal carcinoma
4. Lymphoproliferative disease and lymphoma in the
immunosuppressed.
5. Oral leukoplakia in AIDS patients
6. Chronic interstitial pneumonitis in AIDS patients
 Epidemiology
 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
 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.
 Cases of NPC should be diagnosed by histology.
 PCR
 Vaccination
 There is no vaccine for EBV
 vaccine is being tried in Africa.
Other Human Herpes
Viruses
 Properties of HHV-6 and 7

 Double stranded DNA genome of 170 kbp

 The main target cell is the T-lymphocyte
 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.
 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.
 site of latency T.lymphocytes CD4
Roseala Infantum
 Diagnosis and Management
 PCR & cell culture.
 serology is the mainstay of diagnosis where specific IgM
and IgG are detected.
 Ganciclovir ,foscarnet
 Human Herpes Virus 8
 Originally isolated from cells of Kaposi’s sarcoma (KS)
 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.
Kaposi’s Sarcoma