1. Dr. Amanj Saeed MBCHB, MSc, PhD amanj.saeed@krg.org5
Herpesviruses
Dr. Amanj Saeed
MBCHB, MSc, PhD

2. Herpesviruses herpes viruses are widely disseminated in nature
eight human herpesviruses have been isolated:
herpes simplex virus 1 and 2
varicella zoster virus
human cytomegalovirus
Epstein-Barr virus
human herpesviruses 6 to 8

3. Herpesviruses: definition
Spherical, nm in diameter
herpesviruses contain a linear, ds DNA genome, kbp.
More than 35 proteins in virion.
the genome is packaged into a characteristic 162 capsomere nucleocapsid
the capsid is then enclosed in a viral tegument and a lipid and glycoprotein envelope

6. Herpesvirus DNAs
herpesvirus genomes vary greatly in size, base composition and structure
genomes vary in length from 120 kb to 230 kb and contain different arrangements of unique and repeat sequences

7. Biological Properties
Herpesviruses share three biological properties:
all encode enzymes involved in viral replication
production of infectious virus leads to destruction of the host cell
all establish latent infection which persists for the lifetime of the host

8. Pathogenesis
Cell entry
Expression of viral genes
Host responses

9. Pathogenesis
Cell entry
Expression of viral genes
Host responses

10. Expression of viral genes
Expression of viral genes occurs in a regulated cascade:
immediate early genes: essential for co-ordinate regulation of other viral genes
delayed early genes: encode proteins essential for viral DNA replication
late genes: encode structural proteins

11. Pathogenesis
Cell entry
Expression of viral genes
Host responses

12. Herpes simplex viruses
Primary infection refer to the first infection with either HSV.
Reactivation refer to production of infective virus by a latently infected cells.

13. Herpes simplex viruses Oropharyngeal infection
Primary infection occur in infancy or early childhood.
Occur as a result of close contact with an older person (kissing).
It may be asymptomatic or present as acute gingivostomatitis.
Form vesicles on gum and oral mucosa which eventually break down to form ulcers.
Herpetic lesions affect anterior part of the mouth, involve lips and cirumoral skin.

14. Herpes simplex viruses Oropharyngeal infection
Fever
Difficulty in feeding.
The time from onset to healing is about 2 weeks.
In latter life recurrences manifest around the mouth (lip margin) as a cluster of vesicles heralded some hours previously by an itching sensation.
Recurrences are milder, more localised, and shorter duration than primary infection.
the lesion crust and heal within few days.

15. Herpes simplex viruses
Dermal infection (Nurses, dentists, Wrestlers)
Genital infection
Ophthalmic infection
Meningitis and encephalitis

16. Herpes simplex viruses Genital infection
In children herpetic vulvovaginitis may indicate sexual abuse??
There is a reported relationship of HSV and cervical cancer.

18. Herpes Simplex infection

22. HSV infection in immuno-deficient cases
Cause severe infection in immunodeficient patients.
Common in patients whose cellular immunity impaired by malignant diseases or cytotoxic therapy.
Common in AIDS patients.

23. Herpes simplex viruses Pathogenesis
Reactivation of the virus may occur and could be triggered by:
Cold exposure
Febrile illness
Sunlight
Menstruation
And therapeutic irradiation.

24. Diagnosis Lesion is characteristic.
Diagnosis is necessary in eye and genital infection.
Complement fixation.
ELISA
Virus can be isolated by inoculation of swabs into cell line and observe the characteristic cytopathic effect.
Vigorous scrapping of the base of lesions reveal multinucleate cells containing intra-nuclear inclusions.

25. Diagnosis
Electron microscopy
Immunofluorescence
PCR

26. Treatment Acyclovir (ACV) is the drug of choice.
It is available as : oral, topical, and intravenous preparations.
Normally primary and recurrent infection does not require treatment except immunodifficient patients.
Eye infection can be treated by topical ACV.
ACV in pregnancy is controversial, it can be given in late pregnancy to protect the baby from infection.
Severe generalised infection in immunodeficient patient can be treated by IV ACV (5mg/kg body weight every 8 hours.

27. Varicella-zoster virus
Cause varicella (chicken pox)
Herpes zoster (shingles)

28. Varicella-zoster virus
VZV is endemic in most populations
primary infection is presumed to occur via the respiratory route
at least 10% of the population remain uninfected

29. Varicells (chicken pox )
Acquired by respiratory rote
Virus becomes latent in dorsal root ganglia
May affect any sensory nerve (thoracic, trigeminal, cervical, lumbosacral)
Viral DNA can be detected in sensory ganglia.
Reaction cause the attack of herpes zoster (elderly and immuno- compromised)

31. Varicella (chicken pox )
Common childhood infection
Incubation period of 2 weeks
In children appear as rashes.
Adult suffer more constitutional symptoms.
Rashes are centripetal (more pronounced on the trunk than on limbs)
Macule, papules, vesicles then form crusts that are shed from skin.

32. Complications Bacterial infection leads to formation of pustules
In patients with thrombocytopenia rashes may become haemorrhagic.
Post-infection encephalitis
Pneumonia and generalised varicella in immuno- compromised patients.
Leukaemic children are at particular risk of pneumonitis .

33. Herpes zoster
Zoster derived from Latin words for a belt or girdle and refers to the characteristic distribution of the rash when thoracic dermatomes are involved.
The attack is heralded by hyperaesthesia and some time pain in the affected area followed by appearance of typical herpetic vesicles that eventually crust over and heal.

34. Herpes zoster Complications Post-herpetic pain
Ophthalmic zoster (ophthalmic branch of trigeminal nerve) is affected.
Generalized zoster

36. Treatment Chicken pox Usually does not require antivirus
ACV is useful for both prevention and treatment in immuno-compromised patient
VZV can be treated by ACV (10mg/kg every 8 hours)

37. Beta herpesviruses human cytomegalovirus (HCMV)
human herpesvirus 6 and 7

38. HCMV Human Cytomegalovirus
Prevalence of HCMV in adult populations is 70% and is a result of:
intrauterine infection
perinatal infection
intimate or sexual contact
transfusion of whole blood, cellular products or solid organs

39. Latency
HCMV appears to establish latent infection in cells of the monocyte/macrophage lineage
HCMV must also persist in the cellular fraction of blood and in solid organs

40. Congenital Infection
10% of infected babies are born with disease, including jaundice, growth retardation hepato- splenomegaly and encephalitis
At least 15% of neonates who are apparently asymptomatic develop intellectual impairment

42. Primary Infection

43. Primary infection
primary infection with HCMV is almost always asymptomatic
rarely primary infection leads to a ‘glandular fever’ syndrome:
Sore throat.
Fever.
Lymphadenopathy (tender, enlarged lymph nodes).
General malaise.
Headache.
Muscle aching.
Erythematous rash involving the trunk.

44. Reactivation Disease
pneumonitis, particularly following bone marrow transplantation. Mortality ~80%
colitis
adrenalitis
retinitis, particularly in AIDS patients

46. HHV-6 recently discovered human herpesviruses
infection with HHV-6 is ubiquitous and is the cause of ‘exanthem subitum, roseola infantum ’, a pyrexial illness of infancy (Fever and Rash).
More than 95% of children older than one year and adults are virus positive
Latency occur in gland, kidneys and lymphoid tissues.

47. HHV-6
Reactivation occur after hematopoietic stem cell transplantation (cases delay engrafment, CNS dysfunction, and increased mortality

48. HHV-7 Different from HHV-6. Share 50% homology on DNA level with HHV-6
Infection occurs in early childhood
Persistent infections are established in salivary gland
Primary infection with HHV-7 has been linked with roseola infantum

49. Gammaherpesviruses
Epstein-Barr virus
HHV-8

50. Epstein-Barr virus EBV has a seroprevalence of 80-90%
EBV replicates in epithelial cells of the oro- pharynx
EBV colonizes the memory B-cell where it establishes latent infection, which is characterized by the expression of a limited subset of virus genes, known as the “latent” genes 

51. Diseases
Primary infection with EBV can cause the ‘glandular fever’ syndrome (infectious mononucleosis )
Chronic infection is associated with three important diseases:
Burkitt’s lymphoma
Hodgkin lymphoma and Non-Hodgkin Lymphoma,
nasopharyngeal carcinoma
other lymphomas

52. HHV-8 Also called Kaposi Sarcoma Associated Herpesvirus
The genome is 165 kbp, contain numerous genes related to cellular regulatory genes involved in cell proliferation, apoptosis and host responses.
The virus cause Kaposi Sarcomas (vascular tumors of mixed cellular composition.
Transmitted through oral secretion, sexual contact, blood transfusion, organ transplant, and vertical transmission.