1. Human herpesviruses
Three subfamilies (genome structure, tissue tropism, cytopathologic effect, site of latent infection)
Alphaherpesvirinae:
Human herpesvirus 1 Herpes simplex type 1 HSV-1
Human herpesvirus 2 Herpes simplex type 2 HSV-2
Human herpesvirus 3 Varicella-zoster virus VZV
Gammaherpesvirinae
Human herpesvirus 4 Epstein-Barr virus EBV Oncogenic
Human herpesvirus 8 Kaposi’s sarcoma related virus HHV-8 Oncogenic
Betaherpesvirinae
Human herpesvirus 5 Cytomegalovirus CMV Congenital inf
Human herpesvirus 6Herpes lymphotropic virus HHV-6
Human herpesvirus 7 Human herpesvirus 7 HHV-7

2. Human herpesviruses Large, enveloped double stranded DNA viruses
Icosahedral capsid
Sensitive to acid, solvents, detergents and drying

3. Human herpesviruses They have common: Virion morphology
Basic mode of replication
Capacity to establish latent and recurrent infections, in case of EBV immortalizing infections
Ubiquitous
Usually cause benign disease especially in children
In immunosuppressed people they cause significant morbidity and mortality

6. Human herpesviruses
-DNA polymerase: -viral DNA replication -good target for antiviral drugs.
-DNA replication and assembly:nucleus
-buds from nuclear membrane, released by exocytosis and cell lysis.
-lytic,persistant, latent, for EBV immortalizing infections

7. Herpes simplex virus Two types: HSV-1 and HSV-2
HSV can infect most types of human cells and even cells of other species.
Lytic infection of fibroblasts and epitelial cells but latent infection of neurons
The primary target cell: mucoepitelial cells
Site of latency: neurons

8. Herpes simplex virus
Means of spread: HSV-1 close contact, HSV-2 close contact+sexual transmission!
Generally cause infection at the site of infection
HSV-1: infections above the waist
HSV-2: infections below the waist
Growth characteristics are different
HSV-2 :more potential for viremia

9. Herpes simplex virus
Disease initiates by direct contact, depends on the infected tissue (oral, brain, genital)
Direct cytopathologic effect
Lytic infections of most cells, latent infection of neurons(hides from immune response)
Cell to cell spread-syncytia(avoids antibody)
Cowdry type A acidophilic intranuclear inclusion bodies

10. Herpes simplex virus
Initiates infection through mucosal membranes or breaks in the skin
Virus replicates in the cells at the base of the lession and infects the innervating neurons
Travels by retrograde transport to the ganglion( trigeminal ganglion for oral HSV, sacral ganglia for genital HSV)

12. Herpes simplex virus Then turns to initial site of infection
May be inapparent or vesicular( vesicle fluid contains infectious virons)
Tissue damage: viral pathology+immunopathology
Heals without a scar
Latent infection occurs in neurons

13. Herpes simplex virus Recurrence: stress, trauma, fever, sunlight)
The virus travels back down the nerve causing lessions at the dermatome
Recurrences are less severe and more localized

14. HSV-1 is common
90% have antibody by 2 years of age
HSV-2 occurs later in life with sexual activity
Physicians,nurses,dentists at risk for infection of fingers (herpetic whitlow)
Immunocompromised people and neonates at risk of disseminated, life-threateneing disease.

15. Laboratory diagnosis
Cytology and histology: Tzanck smear(scraping of the base of a lesion), Papanicolaou smear or biopsy specimen
Cytopathic effects: syncytia, ballooning of cytoplasm, Cowdry A intranuclear inclusions
Direct antigen detection: immunofluorescence method or immunoperoxidase method
DNA :in situ hybridization or PCR in tissue or vesicle fluid

16. Laboratory diagnosis Virus isolation: not routine now
Serology:primary infection, type specific antibody by ELISA (differentiates HSV-1 and HSV-2)

17. Varicella-Zoster Chickenpox(varicella)
With recurrence :herpes zoster-shingles:zona
Primary target cell: mucoepitelial cell
Site of latency: neuron
Means of spread: respiratory and close contact
Viremia occurs after local replication :skin lessions over the entire body

18. Varicella-Zoster Primary VZV infection: mucosa of respiratory tract
Viremia
Reticuloendotelial system,liver,spleen
11-13 days later secondary viremia
Virus is spread through the body and skin=rash+fever+systemic symptoms

19. Varicella-Zoster
Latent in dorsal root or cranial nerve ganglia after primary infection
Reactivates in older adults and in patients with impaired immunity.
On reactivation : a vezicular rash along the entire dermatome
Children and leukemia: VZV more serious and more disseminated disease

20. Varicella-Zoster Extremely communicable
Rates of infection exceeds 90% among household contact
Contagious before and during symptoms.
HZ develops in 10-20% of people infected with VZV and contains viable virus.

21. Varicella-Zoster Laboratory diagnosis: Cytology
Virus isolation: difficult
NAT
Serology
Treatment:
ACV,famciclovir and valacyclovir
Prophylaxis: VZIG:varicella-zoster immunoglobulin:immunosuppressed patients
A live attenuated vaccine(Oka strain)

22. Epstein-Barr Virus
Heterophile antibody-positive infectious mononucleosis
Chronic disease
Associated with endemic Burkitt’s lymphoma, Hodgkin’s disease, nasopharyngeal carcinoma, B-cell lymphomas in patients with acquired or congenital immunodeficiencies.
Hairy oral leukoplakia
Mitogen for B cells and immortalizes them

23. Epstein-Barr Virus Gammaherpesvirinae:
Primary target cell: B cells and epitelial cells
Site of latency: B cell
Means of spread: saliva (kissing disease)
Limited host range and tissue tropism: receptor for C3d component of the complement system (CR2 or CD21) which is expressed on B cells of humans and some epitelial cells of oro- and nasopharynx.

24. EBV-associated neoplasms
Geographic distribution
Co-factor?
Endemic Burkett’s lymphoma: Africa:malaria
Nasopharyngeal carcinoma: China

25. Laboratory diagnosis
Heterophile antibody: results from nonspecific activation of B cells by EBV
IgM antibody recognizes Paul-Bunnell antigen on sheep, horse and bovine erythrocytes not on guinea pig kidney cells
Detected at the end of first week , lasts for several months
Monotest, ELISA: specific antibodies
VCA-IgM, antibody to early antigen (EA): recent infection
VCA-IgG, EBNA: previous infection
PCR

26. Cytomegalovirus(CMV)
Betaherpesvirnae: lymphotropic
Primary target cell: monocyte, lymphocte, epitelial cell
Site of latency: monocyte, lymphocyte and?
Means of spread: close contact, transfusions, tissue transplant and congenital

27. Clinical findings Predominant presentation: asymptomatic
Neonates: deafness, mental retardation
Immunosuppressed patients: disseminated dissease, severe disease (pneumonia, retinitis, colitis, esophagitis)

28. Congenital infection An important cause of congenital disease
Serious birth defects is high if primary infection occurs during pregnancy
Microcephaly, intracerebral calcification,hepatosplenomegaly,rash(cytomegalic inclusion disease), unilateral or bilateral hearing loss, mental retardation
CMV in the urine in the first week (culture,PCR)

29. Laboratory tests
Cytology and histology: ‘OWL’s eye’ inclusion body basophilic intranuclear:Urine not so sensitive
Antigen in peripheral leucocytes
DNA by PCR
Cell culture: Human diploid fibroblasts
Serology: primary infection(IgM by ELISA)

30. Human herpesvirus 6 Betaherpesvirinae Lymphotropic , ubiquitous
Primary target cell: T cells and ?
Site of latency: T cells and ?
Means of spread: Respiratory, close contact
Exanthema subitum: roseola
A mononucleosis syndrome and lympadenopathy

31. Human herpesvirus 8
HHV-8 DNA sequences were discovered by PCR in biopsy specimens of
Kaposi’s sarcoma (characteristic opportunistic diseases associated with AIDS)
Primary effusion lymphoma (rare type of B-cell lymphoma)
Multicentric Castleman’s disease

32. Human herpesvirus 8 Kaposi’s sarcoma-related virus
Primary target cell: Lymphocyte and other cells
Site of latency:?
Means of spread: close contact, sexual, saliva?
Limited to certain geographic areas (Italy, Greece, Africa) and AIDS

33. Human herpesvirus 8 Laboratory diagnosis:
Serology: specific antibodies:IFA IgG,IgM
HHV-8 DNA by PCR

34. Antivirals Herpes Simplex 1 and 2 Acyclovir Penciclovir Valacyclovir
Famciclovir
Adenosine arabinoside (ara-A)
Trifluridine

35. Antivirals Varicella-Zoster Virus Acyclovir Famciclovir Valacyclovir
Varicella-zoster immune globulin (VZIG)
Zoster immune plasma
Live vaccine
Epstein-Barr Virus None

36. Antivirals Cytomegalovirus Ganciclovir* Valganciclovir*
Iododeoxyuridine
Foscarnet*
Trifluridine
Cidofovir*

37. Herpesvirus simiae(B virus)
Asian monkeys
Bites, saliva
Encephalopathy in humans
fatal