1. Herpesviruses

2. Herpesviridae
General characteristics
•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.

3. Herpesviridae
3 Sub-families
•Alphaherpesvirinae (HSV-1; HSV-2; VZV)
– Grow rapidly
– Latency in sensory neurons
•Betaherpesvirinae (CMV; HHV-6; HHV-7)
– Grow slowly
– Latency in salivary glands, kidneys, lymphocytes
•Gammaherpesvirinae (EBV; HHV-8/KSHV)
– Lymphoproliferative diseases
– Latency in lymphoid cells

4. Herpesviridae

5. Herpesviridae
HHV-1 Herpes simplex virus type 1 (HSV-1) α 70-90%
Oral, ocular lesions; encephalitis
HHV-2 Herpes simplex virus type 2 (HSV-2) α 30%
Genital lesions; neonatal infections
HHV-3 Varicella zoster virus (VZV) α 95%
Chickenpox; shingles
HHV-4 Epstein-Barr virus (EBV) γ 95%
IM; tumors (B cell, epithelial)
HHV-5 Cytomegalovirus (CMV) β 80%
IM; congenital infections; pneumonia (Tr.)
HHV-6A Human herpesvirus-6A β ~100%
Roseola; MS?; CFIDS?; immunocomp.
HHV-6B Human herpesvirus-6B β ~100%
Disease in immunocomp. hosts
HHV-7 Human herpesvirus-7 β ~100%
some roseola
HHV-8 Kaposi’s sarcoma-associated herpesvirus γ 15%
Tumors (B cell, Kaposi’s sarcoma)

6. Herpesviridae
Structure
•Enveloped
•Double-stranded, linear DNA
•70 to >200 genes
•Encode enzymes involved
in nucleic acid metabolism (e.g.,
thymidine kinase, ribonucleotide
reductase,
DNA polymerase)
From: Principles of Virology: Molecular Biology,
Pathogenesis, and Control. S.J. Flint et al.

7. Herpesviridae
Structure
•Enveloped
•Double-stranded, linear DNA
•70 to >200 genes
•Encode enzymes involved
in nucleic acid metabolism (e.g.,
thymidine kinase, ribonucleotide
reductase,
DNA polymerase)
http://www.stdgen.lanl.gov/stdgen/bacteria/hhv1/herpes.html

8. Herpesviridae
Structure
•Enveloped
•Double-stranded, linear DNA
•70 to >200 genes
•Encode enzymes involved
in nucleic acid metabolism (e.g.,
thymidine kinase, ribonucleotide
reductase,
DNA polymerase)
Linda Stannard, University of Cape Town, S.A

9. Herpesviridae
HHV-1 Herpes simplex virus type 1 (HSV-1) α 152 kb
Oral, ocular lesions; encephalitis
HHV-2 Herpes simplex virus type 2 (HSV-2) α 155 kb
Genital lesions; neonatal infections
HHV-3 Varicella zoster virus (VZV) α 125 kb
Chickenpox; shingles
HHV-4 Epstein-Barr virus (EBV) γ 172 kb
IM; tumors (B cell, epithelial)
HHV-5 Cytomegalovirus (CMV) β 230/236 kb
IM; congenital infections; pneumonia (Tr.)
HHV-6A Human herpesvirus-6A β 159 kb
Roseola; MS?; CFIDS?; immunocomp.
HHV-6B Human herpesvirus-6B β 162 kb
Disease in immunocomp. hosts
HHV-7 Human herpesvirus-7 β 153 kb
some roseola
HHV-8 Kaposi’s sarcoma-associated herpesvirus γ 138 kb*
Tumors (B cell, Kaposi’s sarcoma)

10. Human Herpesvirus
Herpes Simplex Viruses

11. Herpes Simplex Virus
Properties
•Belong to the alphaherpesvirus subfamily
•Double stranded DNA enveloped virus
•Genome of around 150 kb
– HSV-1 and HSV-2 share 50 - 70% homology
•Man is the only natural host for HSV.
•HSV-1 and HSV-2
– Several cross-reactive epitopes within each other
– Antigenic cross-reaction with VZV.

12. Herpes Simplex Virus
Properties
•HSV is spread by contact
– saliva, tears, genital and other secretions
•There are 2 peaks of incidence
– at 0 - 5 years
– late teens (when sexual activity commences)
•HSV-1 causes infection “above the belt”
– Only 40% of clinical isolates from genital sores are HSV-1;
•HSV-2 causes infection “below the belt”
– Only 5% of strains isolated from the facial area are HSV-2;

13. Herpes Simplex Virus
Properties
•Primary infection
– is usually subclinical in most individuals;
– It is a disease mainly of very young children ie. those below 5 years;
– the most common form of infection results from a kiss;
– 10% of the population acquires HSV through the genital route.
•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.

14. Herpes Simplex Virus
From: Principles of Virology: Molecular Biology,
Pathogenesis, and Control. S.J. Flint et al.

15. Herpes Simplex Virus
Properties
•Recurrence
– Associated with physical or psychological stress, infections (especially
pneumococcal and meningococcal) fever, irradiation (including sunlight), and
menstruation.
– 45% of orally infected individuals;
– 60% of patients with genital herpes;
– The mean number of episodes per year is about 1.6…(!?!?!?)

16. Herpes Simplex Virus
From: Principles of Virology: Molecular Biology,
Pathogenesis, and Control. S.J. Flint et al.

17. Herpes Simplex Virus
Clinical Manifestations
•Acute gingivostomatitis
•Herpes Labialis (cold sore)
•Ocular Herpes
•Herpes Genitalis
•Other forms of cutaneous herpes
•Meningitis
•Encephalitis
•Neonatal herpes

18. Herpes Simplex Virus
Diagnostic
•Direct Detection
– Electron microscopy
(rapid result but cannot distinguish
between HSV and VZV)
– Immunofluorescence
(distinguish HSV and VZV)
– PCR
(routine for the diagnosis of
herpetic encephalitis)
•Virus Isolation
– 1 - 5 days
•Serology
– 1-2 weeks before antibodies appear
n:
– Used to document to recent infection.

19. Herpes Simplex Virus
Treatment
Acyclovir – this the drug of choice for most situations at present.
– Intravenous for HSV infection in normal and immunocompromised patients;
– Oral treatment and long term suppression of mucocutaneous herpes and prophylaxis
of HSV in immunocompromised patients;
– Topically for HSV infection of the skin and mucous membranes;
Famciclovir and valacyclovir
– oral only, more expensive than acyclovir.
Other older agents (idoxuridine, trifluorothymidine, Vidarabine (ara-A)

20. Herpes Simplex Virus
De Clercq, E. Nat. Rev. Microbiol. 2:704, 2004.

21. Human Herpesvirus
Varicella Zoster Virus

22. Varicella Zoster Virus
Properties
•Belong to the alphaherpesvirus subfamily
•Double stranded DNA enveloped virus
•Genome of around 123 kb
– Genome size 125 kbp, long and short fragments with a total of 4 isometric forms.

23. Varicella Zoster Virus
Properties
• Varicella (chickenpox) is an endemic disease.
– Highly communicable (attack rate of 90% in close contacts);
•Most people become infected before adulthood
– Classic diseases of childhood;
– Highest prevalence occurring in the 4 - 10 years old age group;
– 10% of young adults remain susceptible;
•Primary Infection
– Entry via the respiratory tract
– Incubation period of 14-21 days
– fever, lymphadadenopathy. and widespread vesicular rashs

24. Varicella Zoster Virus
Properties
•Herpes zoster
– occurs sporadically
– at any age (more frequently >50 years)
•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.
•There is a characteristic eruption of
vesicles in the dermatome which is often
accompanied by intensive pain which may
last for months (postherpetic neuralgia);

25. Varicella Zoster Virus
Complications
•Varicella
– rare but occurs more frequently 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.
•Herpes Zoster
– rare but occurs more frequently in immunocompromised patient;
– Herpes zoster affecting the eye and face may pose great problems;
– Major concerns are: encephalitis and disseminated herpes zoster.

26. Varicella Zoster Virus
Diagnostic
•Direct Detection
– Electron microscopy
(rapid but cannot distinguish between HSV and VZV)
– Immunofluorescence
(distinguish HSV and VZV)
– PCR
(routine for the diagnosis of herpetic encephalitis)
•Virus Isolation
– 2 - 3 weeks
•Serology
– VZV IgG  past infection;
– VZV IgM  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.)

27. Varicella Zoster Virus
Treatment
•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.
•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:
– acyclovir, valicyclovir, and famciclovir;
– little difference in efficacy between them;

28. Varicella Zoster Virus
Prevention
•Preventive measures should be considered for individuals at risk
– leukaemic children, neonates, and pregnant women;
– passive immunization with Zoster immunoglobulin (ZIG) is the preparation of
choice but it is very expensive.
•A live attenuated vaccine is available.
– Great reluctance to use it in the past, especially in immunocompromised
individuals since the vaccine virus can become latent and reactivate later on;
– Recent data suggests that the vaccine is safe.

29. Human Herpesvirus
Cytomegalovirus

30. Cytomegalovirus
Properties
•Belong to the betaherpesvirus subfamily
• Nucleocapsid 105nm in diameter, 162 capsomers
• Double stranded DNA enveloped virus
– long and short segments orientated in either direction

31. Cytomegalovirus
Properties
•Transmitted vertically or horizontally usually with little effect on the host;
– Transmission may occur in utero, perinatally or postnatally;
– Sexual transmission may occur as well as through blood and blood products and
transplanted organ.
•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.
•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.

32. Cytomegalovirus
Properties
•Congenital infection - may result in cytomegalic inclusion disease
– isolation of CMV from the saliva or urine within 3 weeks of birth.
– affects 0.3 - 1% of all live births
– second most common cause of mental handicap after Down's syndrome and
is responsible for more cases of congenital damage than rubella.
•Transmission occur s following primary or recurrent CMV infection.
– May be transmitted to the fetus during all stages of pregnancy;
– 40% chance of transmission to the fetus following a primary infection.;

33. Cytomegalovirus
Properties
•Perinatal infection
– acquired mainly through infected genital secretions, or breast milk;
– 10 times more common
– 2 - 10% of infants are infected by the age of 6 months worldwide
– usually asymptomatic
•Postnatal infection
– mainly occurs through saliv
– usually asymptomatic
– syndrome of infectious mononucleosis may develop

34. Cytomegalovirus
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.

35. Cytomegalovirus
Diagnostic
•Direct Detection
– biopsy specimens may be examined histologically for CMV inclusion
antibodies or for the presence of CMV antigens;
– The pp65 CMV antigenaemia test is routinely used for rapid diagnosis;
– PCR for CMV-DNA...
•Virus Isolation
– requires up to 4 weeks for result.
– rapid culture methods (DEAFF) can provide a result in 24-48 hours.
•Serology
– CMV IgG  past infection;
– CMV IgM  recent primary infection;

36. Cytomegalovirus
Treatment
Anti-CMV agents in current use are ganciclovir, forscarnet, and cidofovir.
•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/postnatal infection - it is usually not necessary to treat
•Immunocompromised patients - it is necessary to make a diagnosis of CMV
infection early and give prompt antiviral therapy;

37. Human Herpesvirus
Epstein-Barr Virus

38. Epstein-Barr Virus
Properties
•Belong to the gammaherpesvirus subfamily
• Nucleocapsid 100nm in diameter, 162 capsomers
• Double stranded DNA enveloped virus
– 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

39. Epstein-Barr Virus
Properties
Two epidemiological patterns are seen with EBV.
•In developed countries (2 peaks of infection)
– 80-90% of adults are infected;
– the first in very young preschool children aged 1-6 years old;
– the second in adolescents and young adults aged 14 – 20
•In developing countries
– 90% of children are seropositive
– infection occurs at a earlier age (<2 years old)

40. Epstein-Barr Virus
Properties
•Transmitted by contact with saliva, in particularly through kissing.
•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.

41. Epstein-Barr Virus
Clinical Manifestations
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.

42. Epstein-Barr Virus
Diagnostic
•Direct Detection
– PCR for CMV-DNA...
– Immunohistochemestry for viral proteins in tissue samples
•Serology
– EBV IgG VCA  past infection;
– EBV IgM VCA  recent primary infection;

43. Epstein-Barr Virus
Prevention
•A vaccine should be able to control both BL and NPC.
– Such a vaccine must be given early in life.
– 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 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.

44. Human Herpesvirus
Other Human Herpesvirus

45. HHV-6 and HHV-7
Properties
•Belong to the betaherpesvirus subfamily
•Double stranded DNA genome of 170 kbp
•Despite related HHV-6 and HHV-7 share limited nucleotide homology and
antigenic cross-reactivity.
•Infect:
– T-lymphocytes (most frequently)
– B-lymphocytes

46. HHV-6 and HHV-7
Properties
•HHV-6 and HHV-7 are ubiquitous and are found worldwide.
– 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.

47. HHV-6 and HHV-7
Clinical Manifestations
•HHV-6 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.
– There are reports that the disease may be
complicated by encephalitis.
•HHV-7 has no firm disease association
•Although both viruses may be reactivated in
immunocompromised patients, it is yet uncertain
whether they cause significant disease since
CMV is almost invariably present.

48. HHV-6 and HHV-7
Diagnosis and Treatment
•Only few virology laboratories offer a diagnostic for HHV-6 or HHV-7
– The technique for virus isolation is complicated
– Therefore serology is the mainstay of diagnosis where specific IgM and IgG are detected.
– Molecular diagnosis has been the best approach
•There is no specific antiviral treatment for HHV-6 and HHV-7 infection.

49. HHV-8 / KSHV
Properties
•Belong to the gammaherpesviruses subfamily
•Originally isolated from cells of Kaposi’s sarcoma (KS)
– firmly associated with Kaposi’s sarcoma as well as some lesser known
malignancies such as Castleman’s disease and primary effusion lymphomas
•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.

50. HHV-8 / KSHV
Properties
•Belong to the gammaherpesviruses subfamily
•Originally isolated from cells of Kaposi’s sarcoma
(KS)
– firmly associated with Kaposi’s sarcoma as well
as some lesser known malignancies such as
Castleman’s disease and primary effusion
lymphomas
•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.