Human Herpesviruses

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Human Herpesviruses

• Dr.Pranee Leechanachai
• Dept. Clinical Microbiology
• Faculty of Associated Medical Sciences
• www.ams.cmu.ac.th
• ???????????????????????? -----gt Teaching slides

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Family Herpesviridae
Morphology
icosahedral capsid (100 nm)
162 capsomers
envelope(150-250 nm)
genomelinear double stranded DNA
Replication
nucleus budding through nuclear membrane
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Herpesvirus Particle
envelope
icosahedral capsid
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Herpesvirus Subfamily

• Alphaherpesvirinae
• HSV-1,HSV-2,Varicella-zoster virus
• Betaherpesvirinae
• Cytomegalovirus, HHV-6, HHV-7
• Gammaherpesvirinae
• Epstein-Barr virus,HHV-8

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Human Herpesviruses (HHV)

• HHV-1 - gt Herpes simplex virus 1
• HHV-2 - gt Herpes simplex virus 2
• HHV-3 - gt Varicella-zoster virus
• HHV-4 - gt Epstein-Barr virus
• HHV-5 - gt Cytomegalovirus
• HHV-6 - gtHumanB cell lymphotropic virus
• HHV-7 - gt isolated from CD4 cell
• HHV-8 - gt Kaposisarcoma associated
• herpesvirus (KSHV)

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Herpes simplex virus (HSV)
Properties
_at_ ectodermal tissue tropism
_at_ vesicle lesion
_at_ infection - gt multinucleated cell
_at_ latency HSV-1- gt trigerminal nerve
ganglia HSV-2- gt lumbosacral nerve ganglia
_at_ recurrent infection stimulistress,fever,sun
light,drugs
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HSV latency
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HSV Diseases
_at_ Acute gingivostomatitis
_at_Herpes labialis
_at_herpes Genital
_at_Neonatal herpes
_at_Herpetic whitlow
_at_Meningitis encephalitis
_at_ Herpetic keratoconjunctivitis
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Acute gingivostomatitis

• primary infection
• HSV-1
• young children 1-6 years
• mucous membrane -gtshallow ulcer
• pharyngitis, tonsillitis
• related agent Coxsackie virus
• -gt herpangina

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Acute herpes gingivostomatitis
Colour Atlas of Infectious Disease, 2003
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Herpes labialis

• Recurrent infection
• HSV-1
• vesicle at lip or
• mucocutaneous junction

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Herpetic whitlow
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Genital Herpes
Vesicle on penis

• HSV-2
• facilitate transmission of HIV

Vesicle on perianal and vulva
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Neonatal herpes
Caused by HSV-2
Intrapartum transmission
Generalized infection
Morbidity 13,000-130,000
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Herpes meningitis encephalitis

• Primary/recurrent infection
• HSV-1/HSV-2
• Mortality rate 60-80

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Herpetic keratoconjunctivitis

• Mostly caused by HSV-1
• primary/recurrent infection
• lesions
• eyelid -gt vesicle
• conjuctiva
• cornea -gt dendritic ulcer

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HSV eye infection
Dendritic ulcer at cornea
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Herpes simplex virus transmission

• Close body contact
• Kissing
• Sexual intercourse
• Intrapartum
• Contaminated materials

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Laboratory Diagnosis of HSV
1. Tzanck test or Papanicolaou staining
2. Antigen detection
Multinucleated cell
3. Antibody detection
4. Virus isolation
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Varicella-Zoster Virus
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Varicella (chickenpox)
Primary infection of VZV
Highest prevalence occurring in children age
4-10 years
Highly communicable disease, attack rate of 90
in close contacts
Incubation period of 14-21 days
Clinical featuresfever, lymphadenopathy,
widespread vesicular rash
Latent in a sensory ganglion
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Varicella skin rash
Varicella,demonstrating all stages of the
rash macules,papules,vesicles
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Pathogenesis of Varicella
Virus latent in sensory ganglion
Dermis skin rash (crops) macule -gt papule -gt
vesicle -gt crust lt ------ 8-12 hr. ---------- gt
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Complications of Varicella
Usually rare but more frequently and greater
severity in immunocompromised patients
Most common secondary bacterial infection of
vesicles
Severe/may be life threatening viral
pneumonia, encephalitis haemorrhagic chickenpox
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Congenital Varicella
Greater risk usually occur in the 1st trimester
of pregnancy with primary infection of VZV
3 chance of transmission to the fetus
recognized congenital varicella syndrome
Varicella syndrome scarring of
skin hypoplasia of limbs brain and eye
defects deafness
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Herpes Zoster (Shingles)
Recurrent infection of VZV
Reactivation of virus in sensory ganglion and
tracks down the sensory nerve to the appropriate
area of the skin
Eruption of vesicle often accompanied with
intensive pain
Usually occur in old age ( gt 50 years)
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Herpes Zoster (shingles)
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Varicella-Zoster
Zoster of the thoracic area, the rash is
distributed in a band round the trunk, it seldom
covers the entire area of skin in a dermatome.
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Varicella-Zoster
Crust lesion of varicella-zoster, a thick plate
of scabs is formed if there damage to the
underlying corium
Vesicular rash confined to the area of skin
supplied by cervical roots 4 and 5.
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Complication of zoster facial paralysis
Zoster of the cervical root C2 and C3, with
facial paralysis and deafness, the patient is
unable to close her right eye and her mouth is
drawn over to the left.
The patient had zoster of the third division of
the fifth cranial nerve (trigeminus), resulted in
facial weakness of lower motor neurome type.
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Laboratory Diagnosis of VZV

• Laboratory confirmation is rarely required in the
  typical varicella
• Direct detection
• electron microscopy vesicle fluid
• immunofluorescence skin scrapping
• Serology
• IgG -gt past infection
• IgM -gt recent primary infection
• Viral isolation rarely used
• (requires 2-4 weeks for results)

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Human herpesvirus 4(Epstein-Barr Virus EBV)
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EBV Infection
Wide spectrum of diseases subclinical -- gt
severe disease
Site of replication oropharynx,salivary
gl.,B-lymphocyte
Lifelong carrier state chronic shedding
Latent infection throat, lymphoid tissue,
B-lymphocyte
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EBV Epidemiology
Ubiquitous adult infection 80-90
Developed countries 2 peaks preschool aged
1-6 years adults aged 14-20 years (80-90 )
Developing countries 90 get infection within
the first 2 years of life
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EBV Transmission

• Saliva through kissing
• Blood transfusion/contact
• cervical secretion
• semen

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EBV Clinical manifestation
Infectious mononucleosis
Burkitts lymphoma
Nasopharyngeal carcinoma
Lymphoproliferative disease lymphoma in
immunosuppressed
Oral leukoplakia in AIDS
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EBV Mononucleosis

• Lymphadenopathy
• Fever,headache, myalgias
• Pharyngitis/tonsillitis
• Lymphocytosis with atypical lymphocyte
• Hepatosplenomegaly (hepatitis)
• Heterophile antibody positive
• Incubation period 30-50 days

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Human herpesvirus 5(Cytomegalovirus CMV)
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Cytomegalovirus

• Cytomegalic infected cells
• large basophilic intranuclear inclusion
• Infection in most organs
• kidney,liver,intestine,lung,brain, salivary
  gland -gt children
• Persistent infection
• chronic infection
• latent infection white blood cells

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Potential sources of virus

• Saliva
• Breast milk
• Blood
• Urine
• Semen/cervical secretion
• Transplanted organs

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CMV Epidemiology

• In developed countries
• with standard hygiene -gt 40
• ultimately -gt 70
• In developing countries
• ultimately -gt over 90
• Lifelong infection
• reactivation are common

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CMV Transmission
In utero
Perinatally
genital secretion, breast milk
2-10 infants infected within 6 months
Postnatally
Saliva, sexual transmission, blood and
transplanted organs
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CMV Clinical manifestation
Congenital infection (0.5-3) 90 are
subclinical at birth 10 may develop severe
disease hepatosplenomegary, jaundice
Infection in normal host gt90 are
subclinical clinical -gt mononucleosis
Infection in immunocopromised host severe
disease,opportunistic infection
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CMV Mononucleosis

• Fever, headache, myalgia
• Lymphocytosisatypical lymphocyte
• Hepatosplenomegaly
• Heterophile antibody negative
• Incubation period 30-40 days

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Human herpesvirus 6
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Human herpesvirus 6

• First isolated from B-lymphocyte in 1986-gt Human
  B lymphotropic virus
• Target cells T-lymphocyte
• B-lymphocyte,monocyte/macrophage, epithelial
  cell
• Latent infection monocyte/macrophage, salivary
  gland

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HHV-6 Clinical Manifestation
Exanthem subitum (roseola infantum)
common in infants age 6-12 mo acute fever 3-5
days skin rash
Mononucleosis-like syndrome lymphadenopathy
and fever
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Human herpesvirus 7

• First isolated from CD4 T cells from healthy
  person in 1990
• Need CD4 receptor for infection
• Infection acquired after 12 mo.
• Virus secreted in saliva
• Clinical manifestation
• exanthem subitum, common cold

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Human herpesvirus 8
Originally isolated from cell of Kaposis
sarcoma (KS)
HHV-8 DNA found in almost 100 in KS
Not ubiquitous infection low seroprevalence in
general population
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Poxviruses
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Poxviruses
Oval or brick shape with envelope
Genome double stranded DNA
Core dumbbell shape
Two lateral bodies
Replicate in cytoplasm
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Poxvirus Particles
Orthopoxvirus 220-450x140-260x140-260nm with
regular spiral filaments 10-20 nm on the surface
Parapoxvirus 250-300x160-190 nm with crisscross
pattern on the surface
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Classification

• Family Poxviridae
• Subfamily Chordopoxvirinae
• Genus Orthopoxvirus
• Genus Parapoxvirus
• Genus Avipoxvirus (fowlpoxvirus)
• Genus Capripoxvirus (sheeppoxlike virus)
• Genus Leporipoxvirus (myxomavirus)
• Genus Suipoxvirus (swinepoxvirus)
• Genus Molluscipoxvirus (molluscum contagiosum
  virus)
• Genus Yatapoxvirus (yabapox and tanapox viruses)

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Classification (cont.)

• Subfamily Entomopoxvirinae
• (insect poxvirus)
• Genus Entomopoxvirus A
• Genus Entomopoxvirus B
• Genus Entomopoxvirus C

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Poxviruses Human pathogens

• Genus Orthopoxvirus
• Variola virus Vaccinia virus
• Monkeypox virus Cowpox virus
• Genus Parapoxvirus
• Orf virus (contagious pustular dermatitis virus)
• Pseudocowpox virus (milkers nodule virus)
• Genus Molluscipoxvirus
• Molluscum contagiosum virus

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Variola Pathogenesis
Dermis macules -gt papules -gt vesicles -gt
pustule-gt crust
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Variola (smallpox)

• Last case in Somalia in 1977
• Successful eradicated by vaccine
• World free from variola in 1979

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Variola evolution of skin rash
papules
vesicles
pustules
crusts
(Emond RTD., A colour atlas of infectious disease
1974)
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Molluscum contagiosum lesions
single umbilicated lesion
pink color dome shaped lesions
(Mandell GL., Atlas of infectious diseases 1996)
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Cowpox lesions
pustule nodule on the hand
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Cowpox Pseudocowpox virus lesion (Milkers
nodule)
Cowpox lesion
Milkers nodule
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Orf virus lesions
Big nodule on finger
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Laboratory Diagnosis

• Direct examination
• Electron microscopy
• Giemsa staining of infected cell scrape
• Virus isolation
• Embryonated egg chorioallantoic membrane
• Cell culture primary monkey kidney cells
• Serology
• hemagglutination inhibition test,
• neutralization test and ELISA

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Cowpox in primary monkey kidney cells,
cytoplasmic inclusions with halo ( Guaneiri
body) (Versteeg J., A Color Atlas of
Virology,1985)
Pocks on chorioallantoic membrane after
innoculation of poxvirus
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infection)
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Human Papillomavirus
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Human Papillomavirus

• Properties
• Icosahedral capsid 45-55 nm
• No envelope
• Genomecircular supercoiled ds DNA 6-8 kb
• Replication in nucleus
• stage of DNA - gt episome or integration
• Tissue tropismreplicate in differentiated cells
• Species specific
• Oncogenicity cervical carcinoma

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Human Papillomavirus

• Classification
• Family Papovaviridae
• Genus Papillomavirus
• human papillomavirus gt 70 genotypes
• Genus Polyomavirus
• BK and JC virus (cause progressive multifocal
  leukoencephalopathy)

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Papillomvirus Particles and genome
E Early genes encode enzymes and regulatory
proteins
L late genes encode viral capsid proteins
E6/E7 (E5) function as viral oncogene
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HPV Pathogenesis
replicate in differentiated epithelial
cells (mature cells)
infect proliferating cells (young cells)
cell proliferation (4-6 weeks after infection)
Infectious virues
spontaneous regression
malignant tumor
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HPV Infection
Common wart
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Diseases caused by human papillomavirus

• Diseases HPV types
• Common warts 2, 4
• Plantar palmar warts 1, 2, 4
• Genital warts 6, 11
• (condyloma acuminata)
• laryngeal papilloma 6,11
• Carcinoma 16, 18
• (cervix, penis)
• Epidermodysplasia verruciformis 5, 8, 9

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Genital Warts
penile wart cauliflower like-lesion
Perianal wart
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Cervical dysplasia caused by papillomavirus
acetowhite lesion of cevix after soaking with 5
acetic acid
Mandell GL., Atlas of infectious diseases 1996)
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Laboratory Diagnosis

• Direct examination
• Electron microscopy
• Papanicolaou smear
• Southern blot/dot blot hybridization
• Polymerase chain reaction (PCR)

PAP smear shows abnormal cells with increase
nuclear cytoplasmic ratio koilocyte
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Adenoviruses
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Adenovirus properties
Icosahedral capsid 70-90 nm with fiber
No envelope
Antigensfiber -gt type specific antigen
hexon - group specific antigen penton- group
specific antigen
Genomelinear double stranded DNA
oncogenic potential
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Adenovirus morphology
Adenovirus particle from electron microscope
Adenovirus structure icosahedral capsid with
penton fiber
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Clinical syndrome
Respiratory infection
Acute febrile pharyngitis -gt ???????????????????
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Pharyngoconjunctival fever (swimming pool
conjunctivitis) ????? ??? ?????? ?? ??????
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Acute respiratory disease ??????? ???????
Pneumonia
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Clinical syndrome
Eye infection
Follicular conjunctivitis ???????????????
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Epidemic keratoconjunctivitis ??????????????????
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Gastrointestinal infection
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Pocks on chorioallantoicnic membrane
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Clinical syndrome

• Gastrointestinal infection
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Genital Warts
Multiple exophytic condylomas
(Mandell GL., Atlas of infectious diseases 1996)
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Genital Warts Vulvo-perineal area
Mandell GL., Atlas of infectious diseases 1996)
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Variola (small pox)
(Emond RTD., A colour atlas of infectious disease
1974)
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Molluscum contagiosum lesions
pink color dome shaped lesions
(Mandell GL., Atlas of infectious diseases.1996)
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Genital Warts (penile area)
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Common Warts
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Human papillomavirus infected cells
Papanicolaou smear shows a clump of abnormal
cells with increased nuclear cytoplasmic ratio
(koilocytes)
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Human Papillomavirus Gemone
E early gene (E1-E7) L late gene E6E7 genes
oncogenes L1L2 encode capsid proteins
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Adenovirus eye infection