Download Human Herpesviruses

Human Herpesviruses
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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
Human herpesvirus 8 Kaposi’s sarcoma related virus HHV-8
• Betaherpesvirinae
Human herpesvirus 5 Cytomegalovirus CMV
Human herpesvirus 6Herpes lymphotropic virus HHV-6
Human herpesvirus 7 Human herpesvirus 7 HHV-7
Herpesviruses
• Unique Features of Herpesviruses
• Herpesviruses have large, enveloped icosadeltahedral capsids containing
double-stranded DNA genomes.
• Herpesviruses encode many proteins that manipulate the host cell and
immune response.
• Herpesviruses encode enzymes (DNA polymerase) that promote viral DNA
replication and that are good targets for antiviral drugs.
• DNA replication and capsid assembly occurs in the nucleus.
• Virus is released by exocytosis, cell lysis, and through cell-cell bridges.
• Herpesviruses can cause lytic, persistent, latent, and, for Epstein-Barr
virus, immortalizing infections.
• Herpesviruses are ubiquitous.
• Cell-mediated immunity is required for control.
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
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Subfamily
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s Alphaherpesvirinae
e Human herpesvirus 1
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Virus
Primary Target Cell
Site of Latency
Means of Spread
Herpes simplex type 1
Mucoepithelial cells
Neuron
Close contact
Human herpesvirus 2
Herpes simplex type 2
Mucoepithelial cells
Neuron
Close contact (sexually transmitted disease)
Human herpesvirus 3
Varicella-zoster virus
Mucoepithelial cells
Neuron
Respiratory and close contact
Human herpesvirus 4
Epstein-Barr virus
B cells and epithelial cells
B cell
Saliva (kissing disease)
Human herpesvirus 8
Kaposi's sarcoma-related
virus
Lymphocyte and other cells
B cell
Close contact (sexual), saliva?
Human herpesvirus 5
Cytomegalovirus
Monocyte, lymphocyte, and epithelial
cells
Monocyte, lymphocyte,
and ?
Close contact, transfusions, tissue transplant, and
congenital
Human herpesvirus 6
Herpes lymphotropic virus
T cells and ?
T cells and ?
Respiratory and close contact?
Human herpesvirus 7
Human herpesvirus 7
T cells and ?
T cells and ?
?
Gammaherpesvirinae
Betaherpesvirinae
icosadeltahedral capsid and an envelope
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
Disease Mechanisms for Herpes Simplex Viruses
Disease
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is initiated by direct contact and depends on infected tissue
(e.g., oral, genital, brain).
Virus causes direct cytopathologic effects.
Virus avoids antibody by cell-to-cell spread (syncytia).
Virus establishes latency in neurons (hides from immune response).
Virus is reactivated from latency by stress or immune suppression.
Cell-mediated immunity is required for resolution with limited role for
antibody.
Cell-mediated immunopathologic effects contribute to symptoms.
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
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
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)
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
Herpes simplex virus
Infects most types of human cells, even cells of
other species.
Lytic infection of fibroblasts and epitelial cells
and latent infection of neurons
HSV-1 binds to heparan sulfate , a proteoglycan
found on the outside of many cell types
Herpes simplex virus
Interacts HveC (herpes virus entry mediator C) : a
member of immunoglobulin protein family similar to
polio virus receptor, found on most cells and neurons
Penetrates by fusion
During latent infection: the only region of genome to
be trancribed generates latency associated
transcripts(LATs) and these RNAs are not translated
in protein
Epidemiology
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Virus causes lifelong infection
Recurrent diseases is source of contagion
Asymtomatic shedding
Saliva, vaginal secretion, lesion fluid
Transmitted orally, sexually, into eye, breaks in skin
HSV-1 usually orally
HSV-2 usually sexually
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.
Clinical Syndromes
• HSV-1 and HSV-2 are common human pathogens
• Painful but benign manifestations and recurrent
disease
• A clear vesicle on an erythematous base
• Pustular lesion, ulcer, crusted lesion
• Sinificant morbidity and mortality on infection of
eye,brain or on disseminated infection in
immunosuppressed person or neonate.
Clinical Syndromes
• Primary herpetic gingivostomatitits
• Recurrent mucocutaneous HSV(cold sores, fever
blister)
• Herpes pharyngitis
• Herpetic keratitis: corneal damage leading to
blindness
• Herpetic whitlow
• Eczema herpeticum
• Genital herpes mostly by HSV-2
Clinical Syndromes
-Herpes encephalitis: usually by HSV-1,the most
common viral cause of sporodic
encephalitis.Mortality is high.
At all age, at any time of year
-HSV meningitis: complication of genital HSV-2
-Neonatal infection: HSV-2, usually fatal
Neonatal HSV
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HSV-2
Either during passage through genital tract
Or rarely in utero
Postnatally from family or hospital personel
Immune system weak
Disseminates to organs
Baby is septic and vesicular lesions
Death,or mental retardation or neurological disability
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
Laboratory diagnosis
• Virus isolation: CPE in 1-3 days in HeLa, Hep-2
cells, human embryonic fibroblasts and rabbit
kidney cells. Isolates are identified by
immunologic methods by antigen detection by
IFA.
• Serology:primary infection, type specific
antibody by ELISA (differentiates HSV-1 and
HSV-2)
Approach
Test/Comment
Direct microscopic examination of cells
from base of lesion
Tzanck smear shows multinucleated giant cells and
Cowdry type A inclusion bodies.
Cell culture
HSV replicates and causes identifiable cytopathologic effect in
most cell cultures.
Assay of tissue biopsy, smear,
cerebrospinal fluid, or vesicular fluid for
HSV antigen or genome
Enzyme immunoassay, immunofluorescent stain, in situ DNA
probe analysis, and polymerase chain reaction (PCR).
HSV type distinction (HSV-1 vs. HSV-2)
Type-specific antibody, DNA maps of restriction enzyme
fragments, sodium dodecyl sulfate-gel protein patterns, DNA
probe analysis, and PCR.
Serology
Serology is not useful except for epidemiology.
Treatment
• Nucleotide analogues, viral DNA polymerase
inhibitors
• Prevents or shortens the course of primary or
recurrent disease
• Can not eliminate latent infection
Treatment
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Acyclovir
Penciclovir
Valacyclovir
Famciclovir
Adenosine arabinoside
Iododeoxyuridine
Trifluridine
FDA-Approved Antiviral Treatments for Herpesvirus Infections
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Herpes Simplex 1 and 2
Acyclovir
Penciclovir
Valacyclovir
Famciclovir
Adenosine arabinoside
Iododeoxyuridine
Trifluridine
Varicella-Zoster Virus
Acyclovir
Famciclovir
Valacyclovir
Varicella-zoster immune globulin
Zoster immune plasma
Live vaccine
Epstein-Barr Virus
None
Cytomegalovirus
Ganciclovir*
Valganciclovir*
Foscarnet*
Cidofovir*
Pregnant women
• Active genital HSV
• Asymtomatic shedding
• Such transmission can be prevented by
cesarean section
• No vaccine available yet.
Varicella-Zoster
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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
Disease Mechanisms of Varicella-Zoster Virus (VZV)
Initial
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replication is in the respiratory tract.
VZV infects epithelial cells, fibroblasts, T cells, and neurons.
VZV can form syncytia and spread directly from cell to cell.
Virus is spread by viremia to skin and causes lesions in successive
crops.
VZV can escape antibody clearance, and cell-mediated immune
response is essential to control infection. Disseminated, life-threatening
disease can occur in immunocompromised people.
Virus establishes latent infection of neurons, usually dorsal root and
cranial nerve ganglia.
Herpes zoster is a recurrent disease; it results from virus replication
along the entire dermatome.
Herpes zoster may result from depression of cell-mediated immunity and
other mechanisms of viral activation.
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
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
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.
Varicella(Chickenpox)
• Five classic childhood exanthems: chickenpox,
measles, roseola, fifth disease,rubella
• Mild childhood disease
• Fever+maculopapular rash
• 14 days incubation
• All stages of skin lesion (vesicle, pustular, crust)
• More severe on trunk even on scalp
• Bacterial superinfection
Varicella(Chickenpox)
• Severe in adults (interstitial pneumonia)
• Severe in neonates and immunocompromised.
Herpes-zoster
• Recurrence of latent varicella
• Severe pain
• Rash limited to the dermatome
Varicella-Zoster
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Laboratory diagnosis:
Cytology
Virus isolation: difficult
Serology
Treatment:
ACV,famciclovir and valacyclovir
Prophylaxis: VZIG:varicella-zoster
immunoglobulin:immunosuppressed patients
• A live attenuated vaccine(Oka strain)
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
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.
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Select viral genes are expressed, depending on the state of the B cell; they include
Epstein-Barr nuclear antigens (EBNAs) 1, 2, 3A, 3B, and 3C; latent proteins (LPs);
latent membrane proteins (LMPs) 1 and 2
The EBNAs and LPs are DNA-binding proteins that are essential for establishing and
maintaining the infection (EBNA-1), immortalization (EBNA-2), and other purposes.
The LMPs are membrane proteins with oncogene-like activity. These proteins
stimulate the growth of and immortalize the B cell.
EBV establishes latency in memory B cells in which only the EBNA-1 and LMP-2 are
expressed, maintaining the genome in the cells but with minimal potential for
immune recognition of the infected cell.
Disease Mechanisms of Epstein-Barr Virus
•Virus in saliva initiates infection of oral epithelia and spreads to B cells in lymphatic
tissue.
•There is productive infection of epithelial and B cells.
•Virus promotes growth of B cells (immortalizes).
•T cells kill and limit B-cell outgrowth. T cells are required for controlling infection.
Antibody role is limited.
•EBV establishes latency in memory B cells and is reactivated when the B cell is
activated.
•T-cell response (lymphocytosis) contributes to symptoms of infectious
mononucleosis.
•There is causative association with lymphoma in immunosuppressed people and
African children living in malarial regions (African Burkitt's lymphoma) and with
nasopharyngeal carcinoma in China.
EBV
•The diseases of EBV result from either an
overactive immune response (infectious
mononucleosis) or
•the lack of effective immune control
(lymphoma and hairy cell leukoplakia).
Epstein-Barr Virus
EBV activate B-cell growth and prevents
apoptosis(programmed cell death)
T cell response (lymphocytosis) :atypical
Lymphocytosis:Downey cells account for 1080% of total white blood cells during the
second week
Lymph glands,spleen and liver swells
Mild in children
Epstein-Barr Virus
Virus causes lifelong infection
May cause aymptomatic shedding
Recurrent disease is a cause of contagion
Children:mild or asmptomatic
Teenagers and adults: infectious mononucleosis
Immunocompromised people: at high risk of for
life threatening neoplastic disease
Diagnosis of Epstein-Barr Virus
1.Symptoms
a.Mild headache, fatigue, fever
b.Triad: Lymphadenopathy, splenomegaly, exudative pharyngitis
c.Other: Hepatitis, ampicillin-induced rash
2.Complete blood cell count
a.Hyperplasia
b.Atypical lymphocytes (Downey cells) (T cells)
3.Heterophile antibody (transient)
4.EBV-antigen specific antibody
• post-transplant lymphoproliferative disease
• Many Hodgkin's lymphomas can also be
attributed to EBV
• Hairy Oral Leukoplakia
EBV-associated neoplasms
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Geographic distribution
Co-factor?
Endemic Burkett’s lymphoma: Africa:malaria
Nasopharyngeal carcinoma: China
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
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
Sources of infection
• Neonate: transplacental transmission,
intrauterine infection, cervical secretion
• Baby or child: body secretions, breast milk,
saliva, tears, urine
• Adult: sexual transmission(semen), blood
transfusion, organ graft
Clinical findings
• Predominant presentation: asymptomatic
• Neonates: deafness, mental retardation
• Immunosuppressed patients: disseminated
dissease, severe disease (pneumonia, retinitis,
colitis, esophagitis)
CMV
• the most common viral cause of congenital
defects
• particularly important as an opportunistic
pathogen in immunocompromised patients
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)
CMV immunsupressed patients
• CMV disease of the lung (pneumonia and
pneumonitis) is a common outcome in
immunosuppressed patients
• Retinitis (%10-15 AIDS patients)
• Interstitial pneumonia and encephalitis
• colitis or esophagitis may develop in as many
as 10% of patients with AIDS
• May be related with GVHR after bone marrow
transplantation
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Immunosuppressed
Patients
Tissue
Children/Adults
Predominan
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presentation
Asymptomatic
Disseminated
disease, severe
disease
Eyes
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Chorioretinitis
Lungs
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Pneumonia,
pneumonitis
Gastrointesti
nal tract
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Esophagitis, colitis
Nervous
system
Polyneuritis, myelitis
Meningitis and
encephalitis, myelitis
Lymphoid
system
Mononucleosis syndrome, posttransfusion syndrome
Leukopenia,
lymphocytosis
Major organs
Carditis,* hepatitis*
Hepatitis
Neonates
Deafness, intracerebral calcification,
microcephaly, mental retardation
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. Epidemiology of Cytomegalovirus Infection
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Disease/Viral Factors
•Virus causes lifelong infection.
•Recurrent disease is source of contagion.
•Virus may cause asymptomatic shedding.
Transmission
•Transmission occurs via blood, organ transplants, and all secretions (urine, saliva, semen, cervical
secretions, breast milk, and tears).
•Virus is transmitted orally and sexually, in blood transfusions, in tissue transplants, in utero, at
birth, and by nursing.
Geography/Season
•Virus is found worldwide.
•There is no seasonal incidence.
Who Is at Risk?
•Babies.
•Babies of mothers who experience seroconversion during term: At high risk for congenital defects.
•Sexually active people.
•Blood and organ recipients.
•Burn victims.
•Immunocompromised people: Symptomatic and recurrent disease.
Modes of Control
•Antiviral drugs are available for patients with acquired immune deficiency syndrome.
•Screening potential blood and organ donors for cytomegalovirus reduces transmission of virus.
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
Treatment
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Ganciclovir
Foscarnet
Valganciclovir
Cidofovir
No vaccine
Other mononucleosis causes
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EBV
CMV
HIV
Toxoplasma gondii
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
Exanthema subitum
• High fever+rash for 24-48 hours
• Incubation 4-7 days
• Recovery without complication
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 Bcell lymphoma)
• Multicentric Castleman’s disease
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
Human herpesvirus 8
• Laboratory diagnosis:
• Serology: specific antibodies:IFA IgG,IgM
• HHV-8DNA by PCR
Herpesvirus simiae(B virus)
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Asian monkeys
Bites, saliva
Encephalopathy in humans
fatal