Herpesviruses

Beta and Gamma

Properties of Cytomegalovirus (CMV)
• A betaherpesvirus subfamily
• Characterized by
• Nuclear inclusions (owl eye cells)
• CMV produces perinuclear cytoplasmic
inclusions and enlargement of the cell
(cytomegaly), a property that gives the virus
its name.
 Owl's-Eye Cells. The photomicrograph shows a section of kidney taken at
autopsy from a three-month-old boy who died of disseminated cytomegalovirus
infection contracted in utero. A single periglomerular renal tubule contains
large, intranuclear viral inclusion bodies typical of those found in cells infected
with cytomegalovirus..).
 Epidemiology
• CMB is ubiquitous
• Age specific prevalence rates show 10-15% are infected with
CMV during the first 5 years of life after which the rate of
new infections levels off.
• The rate increases by 1-2%m per year during adulthood.
• CMV has been isolated from urine, saliva, semen and cervical
secretions
Transmission
May occur in utero, perinatally or postnatally.
– Perinatal infection is acquired mainly through infected
genital secretions, or breast milk.
– Postnatal infection mainly occurs through saliva.
Viral latency in leukocytes with latent infection as seen in
• Sexual contact
• Blood and blood products
• Transplanted organ
 Pathogenesis
• Life long carrier state
• Reactivation
– Infectious virion appear in the urine and the saliva
– Can also lead to vertical transmission
• Re-infection
• Can occur with another or the same strain of CMV

 In developed countries 70% of adult have developed Ab

 In developing countries, over 90% of people are
infected.
 Clinical Manifestations
• Congenital infection
– May result in cytomegalic inclusion disease
• Perinatal infection - usually asymptomatic
• Postnatal infection - usually asymptomatic.
However;
– Infectious mononucleosis syndrome in a minor
no of cases:
• Fever
• Lymphadenopathy
• Splenomegaly
• Immunocompromised patients pneumonitis,
retinitis, colitis, and encephalopathy.
 Congenital Infection

• Defined as the isolation of CMV from the saliva or urine within

3 weeks of birth.
• May be transmitted to the foetus during all stages of pregnancy
• Commonest congenital viral infection; affects 0.3 - 1% of all live
births.
• The second most common cause of mental handicap after
Down's syndrome
• Responsible for more cases of congenital damage than rubella
 Cytomegalic Inclusion Disease

Characterized by:
• Involvement of CNS: Significant defects within 2
years of life
– Severe hearing loss
– Ocular abnormalities
– Mental retardation
• Involvement of reticuloendothelial system
 Laboratory diagnosis
Lab diagnosis of CMV infections depends on

3. Detecting of CMV Cytopathology, antigens or DNA

in infected tissues

5. Isolating the virus from tissue or secretions

7. Demonstrating seroconversion
 Laboratory Diagnosis (1)
• Direct detection
– Histology of biopsy specimens for CMV inclusion
– The detection of CMV antigenaemia is now
routinely used for the rapid diagnosis of CMV
infection in immunocompromised patients
– PCR for CMV-DNA is diagnostic
• Virus Isolation
– Cell culture is regarded as gold standard but
requires up to 3-4 weeks for CPE
– Rapid culture methods such as shell vials can
reduce the time for detection to 24-48 hours
• Serology
– CMV IgG antibody indicates past infection
– CMV IgM is indicative of primary infection
 Laboratory interpretations

• Congenital infection
Virus culture or viral DNA assay positive at birth or within 1-2
weeks
• Perinatal infection
Culture-negative specimens at birth but positive specimens at 4
weeks or more after birth suggest natal or early postnatal
infections
• CMV mononuclesis in non-immunocompromised patients
Serconversions and presence of IgM specific for CMV are the best
indicators of primary infections
• Immunocompromised patients
Demonstration of virus by viral antigen, DNA, or demonstration
of inclusions in diseased tissue.
 Treatment

Congenital infections

• Not usually possible to detect

Perinatal and postnatal infection

• Usually not necessary to treat

Immunocompromised patients

• Is necessary to make a diagnosis give prompt

antiviral therapy: ganciclovir, forscarnet, and
cidofovir
 Prevention

• No licensed vaccine is available

• There is a candidate live attenuated vaccine
• Prevention of CMV disease in transplant
recipients
– 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
– Prophylaxis with acyclovir and ganciclovir
 Other Human Herpes Viruses
HHV-6 and 7

• Properties of HHV-6 and 7

• betaherpesviruses
• HHV-6 and HHV-7 are found worldwide.
• The main target cell is the CD4 † T-lymphocyte
• Transmission by droplet infection (isolated from
saliva and the throat)
 HHV-6
• Infection is common in infancy, almost all of the
population has Ab to this virus by the age of 5 Y.

Clinical Manifestations
• Primary HHV-6 infection is associated with Roseala
Infantum (or fourth disease), which is a classical
disease of childhood.
• Children are protected by maternal Ag until 6 months.
• A spiking fever develops over a period of 2 days
followed by a faint maculopapular rash from trunk to
extermities.
• May be complicated by encephalitis
• Reactivation is common in immuno-suppression (post-
transplantation)
Diagnosis
• Primary infection can be
documented serologically
• Active virus infection can be
documented by culture or DNA
detection (by PCR)
Treatment
Definitive therapy has not been
established, but HHV-6 is more
susceptible to ganciclovir

Roseala Infantum
 HHV-7

• HHV-7 is similar to HHV-6

• HHV-7 is distinct from all human herpesviruses and it
is most closely to HHV-6 and CMV
• Despite the similarities between HHV-6 and HHV-7,
their antigenic diversity is such that Ab to one virus
do not protect from against infection from the other
• No treatment have been identified
 Epstein-Barr Virus (EBV)
Gammaherpesviruses

Epidemiology
• Two epidemiological patterns are seen with EBV
• In developed countries,
• 2 peaks of infection are seen:
– 1st preschool children aged 1 - 6
– 2nd 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

• A lifelong carrier state

• 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: 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
 Disease Association

1. Infectious Mononucleosis
2. Chronic infectious mononucleosis
3. Burkitt's lymphoma
4. Nasopharyngeal carcinoma
5. Lymphoproliferative disease and lymphoma in the
immunosuppressed.
6. X-linked lymphoproliferative syndrome
7. Oral leukoplakia in AIDS patients
8. Chronic interstitial pneumonitis in AIDS patients.
 Infectious Mononuclosis (IM)

• Primary infection is usually subclinical in

childhood
• In adolescents and adults, there is a 50%
chance of IM
• Features include:
– Fever
– Lymphadenopathy
– Splenomegaly
– Usually a self-limiting disease
• Jaundice (in some patients)
 Infectious Mononuclosis (IM)

• Complications are rare:

– Splenic rupture
– Meningoencephalitis
– Pharyngeal obstruction
• Chronic IM may occur in some patients who have
lymphoproliferative disease or lymphoma
 Burkitt’s Lymphoma (BL)

• Endemic in parts of Africa (where

it is the commonest childhood
tumour) and Papua New Guinea
• Usually in age 3-14 years
• Responds well to chemotherapy
• It is restricted to areas with
malaria: may be a cofactor.
• In theory BL can be controlled by the
eradication of malaria (as has happened
in Papua New Guinea) or vaccination
against EBV
 Nasopharyngeal Carcinoma (NPC)
• 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.
• NPC usually presents late and thus the prognosis is
poor.
 Immunocompromised Patients
• Transplant recipients e.g. renal
– Associated with lymphoproliferative disease and
lymphoma
• AIDS patients
– 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
 Diagnosis

• Laboratory analysis of EBV is usually usually documented

by the demonstration of

b) Demonstration of atypical lymphocytes (Downey cell)

c) The heterophil antibody test
d) Anti-EBV IgM

• Burkitt’s lymphoma: Histology

• NPC
– Histology
– The determination of the titre of anti-EBV viral
caspid antigen (VCA) IgA in screening for early
lesions of NPC
 This so-called "Downy cell" is typical of lymphocytes infected by EBV
(Epstein Barr Virus) or CMV (Cytomegalovirus) in infectious
mononucleosis.

•
 Vaccination

• A vaccine against EBV which prevents primary

EBV infection should be able to control both BL
and NPC
• Must be given early in life to:
– Seronegative organ transplant recipients
– Those developing severe IM
• This vaccine is being tried in Africa.
 Human Herpes Virus 8

• Gammaherpesviruses
• Associated with 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
•

• Kaposi's Sarcoma - Close-Up

Close-up
 Human Herpesviruses
Designation Common name Disease

HHV-1 Herps simplex virus-1 Oral (fever blister), ocular lesions, encephalitis

HHV-2 Herps simplex virus-2 Genital, anal lesions, severe neonatal infections,
meningitis
HHV-3 Varicella-Zoster virus Chicken box (primary infection),. Shingles
(reactivation)
HHV-4 Epstein-Barr virus IM (primary infection). Tumors including B-cell
tumors (Burkitt’s lymphoma, immunoblastic
lymphomas of immunosuppressed), NPC
HHV-5 Cytomegalovirus Mononucleosis, severe congential infections.
Infections in immunocompromised (GIT, retinitis,
pneumonia)
HHV-6 Human herpesvirus-6 Roseola in infants (Primary Infection)
Infections in allograft recipients (pneumonia, marrow failure)
HHV-7 Human herpesvirus-7 Some cases of roseola (primary infection)

HHV-8 Kaposi’s sarcoma Tumors, including Kaposi’s sarcoma, Some B-cell

associated herpesvirus lymphomas
(KSHV), human
herpesvirus-8

HHV-1,2,3 are alpha group

HHV-5,6,7 are beta group
HHV-4 and 8 are gamma group
 Learning assessment
1. Which opportunistic infections or conditions are used as indicators for
AIDS?
2. Which immunologic markers are used to diagnose a HIV infections?
3. Which viral agent is suspected to cause meningitis in patients who have
AIDS or have had transplants?
4. Which infection do EBV produce? Which complications may result from
EBV infections?
5. How is an acute viral hepatitis B infection differentiated from a chronic
infection? Which marker indicate the resolution of the infection?
6. What is the method used to identify the rabies virus?
7. Which viruses comprise the enteroviruses?
8. What is the fifth disease ? What is the causes of this disease?
9. What are arenaviruses?
10. Which types of infections do papillomaviruses produce?
11. Which virus has the potential for latency?
12. Why vaccine for influenza not always effective?
13. Which antiviral agents has been developed, and which specific viral
agents are they used?