Transcript Human Herpesviruses

Human herpesviruses
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Three subfamilies (genome structure, tissue
tropism, cytopathologic effect, site of latent
infection)
Alphaherpesvirinae:
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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
Human herpesviruses
Large, enveloped double stranded DNA
viruses
 Icosahedral capsid
 Sensitive to acid, solvents, detergents
and drying
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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
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
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
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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
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Herpes simplex virus
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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
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)
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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
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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
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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.
Laboratory diagnosis
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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
Laboratory diagnosis
Virus isolation: not routine now
 Serology:primary infection, type specific
antibody by ELISA (differentiates HSV-1
and HSV-2)
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Varicella-Zoster
Chickenpox(varicella)
 With recurrence :herpes zostershingles: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
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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
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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
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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.
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Varicella-Zoster
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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)
Epstein-Barr Virus
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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
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.
EBV-associated neoplasms
Geographic distribution
 Co-factor?
 Endemic Burkett’s lymphoma:
Africa:malaria
 Nasopharyngeal carcinoma: China
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Laboratory diagnosis
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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
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
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Clinical findings
Predominant presentation: asymptomatic
 Neonates: deafness, mental retardation
 Immunosuppressed patients:
disseminated dissease, severe disease
(pneumonia, retinitis, colitis, esophagitis)
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Congenital infection
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An important cause of congenital disease
Serious birth defects is high if primary infection
occurs during pregnancy
Microcephaly, intracerebral
calcification,hepatosplenomegaly,rash(cytomega
lic inclusion disease), unilateral or bilateral
hearing loss, mental retardation
CMV in the urine in the first week (culture,PCR)
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)
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Human herpesvirus 6
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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
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
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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
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Human herpesvirus 8
Laboratory diagnosis:
 Serology: specific antibodies:IFA IgG,IgM
 HHV-8 DNA by PCR
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Antivirals
Herpes Simplex 1 and 2 Acyclovir
 Penciclovir
 Valacyclovir
 Famciclovir
 Adenosine arabinoside (ara-A)
 Trifluridine
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Antivirals
Varicella-Zoster Virus Acyclovir
 Famciclovir
 Valacyclovir
 Varicella-zoster immune globulin (VZIG)
 Zoster immune plasma
 Live vaccine
 Epstein-Barr Virus None
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Antivirals
Cytomegalovirus
 Ganciclovir*
 Valganciclovir*
 Iododeoxyuridine
 Foscarnet*
 Trifluridine
 Cidofovir*
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Herpesvirus simiae(B virus)
Asian monkeys
 Bites, saliva
 Encephalopathy in humans
 fatal
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