Herpesviruses Flashcards
What kind of infection is established by herpes viruses
establish life long persistent infections in host w periodic reactivations
Names the subfamillies of herpesviridae(family)
1.Alphaherpesvirinae
2.Gammaherpesvirinae
3.Betaherpesvirinae
Which viruses are in alphaherpesvirinae
HSV 1
HSV2
Varicella Zoster virus
Which Genus is HSV viruses in
simplex virus
Which genus is varicella zoster virus in
varicellovirus
Which viruses are in gammaherpesvirinae /
HHV-4 (Epstein-Barr virus)
HHV-8 (kaposi-sarcoma related virus)
What genus is HHV-4 in
lymphocryptovirus
which genus is HHV-8 in
rhandinovirus
Which viruses are in betaherpesvirinae
HHV-5 (cytomegalovirus)
HHV-6 (Herpes lymphotropic virus)
HHV-7
which genus is HHV-5 in
Cytomegalovirus
Which genus is HHV-6 & HHV-7 in
Roseolovirus
Whats the difference between the alphaherpesvirinae & betaherpesvirinae
A = fast growing + cytolytic
B= slow growing
Which viruses in the Herpes viruses is cytolytic
All alphaherpesvirinae
Which viruses in the herpesvirinae are lymphoproliferative
HHV-4
HHV-6
HHV-7
Which viruses in Herpesvirinae are cytommegalic
HHV-5
Where do HSV-1 & HSV-2 establish latency
in nerve cells
Ho many hours does it take for HSV-1&2 take to complete replication cycle
8-16hrs
What is the target cell for the HSV-1& 2
Mucoepithelial cells
What are the portals of entry for HSV 1&2
Skin
mucous membranes
What is the pathogenesis for HSV-1&2
Skin - replicate in mucoepithelial cell - inaved local nerve endings - retrograde flow - to dorsal root ganglia (trigeminal/sacral) where latency established
What causes reactivation of HSV-1 /2
physical stress
infection via (e.g surgery)
fever
Irradiation
menstraul cycle
What happens during HSV-1 & 2 reactivation
viruses travel via anterograde transport to the peripheral site causing replication to occur in skin & mucous membrane leading to :
-cold sores
- viral shedding
- epithelial cell death
What is the epidemiology of HSV-1& 2
-incidence?
-recurrence
HSV-1 = occurs early in life - young children (6-3yrs) - but stays latent for a lifetime
2 peak incidence = 0-5 & late teens
Recurrences = 45% orally infected & 60% genital herpes
How is HSV-1 & HSV-2 spread?
HSV-1 = infected secretions ( saliva , tears , hand to mouth , kiss
HSV-2 = genital via sex : oral sex - thus can also be orally infected
What are clinical presentations of HSV-1
1.Herpes Gingivostomatitis ( pain + bleeding gums)
2.Herpes Labialis ( cold sore ) - vesicle on lip - occur as recurrence of oral HSV
3.Ocular herpes/Keratoconjunctivitis - hand to eye
4. Herpes Whitlow = abrasion on skin & HSV enters - dentist + hospital personell - vesicle appears
5.Herpes gladiatorum - mucocutaneous infection of thorax, ear, nose , face & hands - wrestlers
6.Eczema herpeticum - infection w HSV on pple w eczema
7.(Sporadic) Encephalitis - swelling of brain
Symptoms of Herpes Simplex Encephalitis
fever
headache
seizures
focal temporal neurologic signs
imparied consiousness
Clinical presentation of HSV-2
- Genital herpes - ulcerative lesion penis , vagina , cervix ,vulva, perinuem , sacral n roots , spinal & meninges
- Neonatal herpes
How is neonatal herpes acquired
from mother : inutero , during birth , after birth
What are the 3 category of neonatal herpes exhibited ?
- Lesion localized to skin
2.Encephalitis w/wo localised skin lesion
3.Disseminated disease involving multiple organs + cns
Which people with a compromised immunity are at risk on infection with Herpes simples virus
1.malnourished children
2.transplanted patients
3.AID patient
Whats the immunity like for people with Herpes simplex virus
-HSV -1 antibodies appear in childhoos & HSV-2 appear adolesence
-Primary infection: IgM ; IgG & IgA persist for long period
-Cell mediated & nonspecific host factors
How can HSV-1 & HSV-2 be diagnosed ?( in the lab)
1.PCR = specific + sensitive =PCR on CSF with large numbers of RBCs found in CSF
for genital infections – Tzank smear to show the formation of multinucleated giant cells
2. Cowdry type A intranuclear inclusions has been largely replaced by immunofluorescent staining, which can distinguish HSV-1 from HSV-2
3.Isolation & identiification of virus - identified by neutralization test/immunimmunofluorescence stain w specific antiserum
4.serology
5.cytopathology
how is serology of HSV-1 & HSV2 LIMITED ?
limited by cross reactivity of HSV-1/2 (share antigens) also in the case of VZV people infected with HSV due to heterotypic anamnestic response ( this is where the immune system responds to pathogen but on a previous encounter w a different but structurally related pathogen - boost your immunity as it protects you from a pathogen that you havent even encountered yet )
after staining the blood smear / vesicle from HSV1 & HSV2
presence of multinucleated giant cells = HSV-1 , HSV-2/ varicella zoster
Treatment of HSV-1 & HSV-2
-acyclovir
-valocyvlovir , vidarabine ( used when there is resistance to acyclovir
how does acyclovir work?
-nucleoside analog - its monophorsphorylated by HSV thymidine kinase & then converted to triphosphate from by cellular kinases
-acyclovir triphosphate incorporated into into viral DNA by HSV polymerase which prevents chain elongation
Difference between varicella & zoster ? And are they caused by the same virus?
varicella = primary infection + acute
Zoster = reactivation of varicella latent virus in neurons
YES caused by same virus
Which cells can vzv virus be grown in
• can be grown in cultures of human fibrioblasts , human amnion or HeLa cells
Pathogenesis of VZV
target cell = mucosa of upper Respiratory tract /conjunctiva
replicate in lymoh nodes
primary viremia spread virus to replicate in liver & spleen
secondary viremia - mononuclear cells infected & transport virus to skin = RASH
latency established via retrograde transport in sensory ganglia
Where is latency established in VZV
sensory ganglia
how reactivation of vzv happens
triggered by stimulus
travel via anterograde transport from dorsal ganglia to dermatome region innervated by the single nerve
causing severe pain in the area
What is the spinal cord segment + nerve that is most commonly causing pain in the area they innervate when VZV reactivated
T3-L3
Trigeminal nerve ( esp opthalmic branch )
whats the epidemiology of vzv
varicella = children disease
• Zoster = more in adults (10-20%) , usually >50yrs
How is VZV spread
airdroplets
direct contact
What are clinical presentations for varicella
1.chicken pox - rash + vesicles - last 5 days - infectious 48hr prior rash till vesicles crust
2.Varicella Pneumonia = common in neonates , adults & immunocompromised patients
whats the incubation period for VZV
10-21 days
What are clinical presentation of Herpes zoster
1.Severe pain - in area of skin/mucosa supplied by one or more groups of sensory nerves & ganglia and is unilateral - vesicles appear over skin supplied by affected nerves
2.Postherpetic pain- (seen in elderly adults) - protrcted pain that may continue for months
- MC after opthalmic zoster & around the eye
3.Zoster Opthalmicus - reactivation virus in opthalmic div of trigeminal n
- painful blisters on one side of forehead
4.Ramsay Hunt syndrome (herpes Zoster oticus)
• reactivation of latent VZV in geniculate ganglion of facial nerve
5.Varicella Zoster CNS disease (Meningitis)- can present w/wo rashes
whats the immunity like for VZV
• Previous infection w varicella has lifelong immunity to varicella
• Antibodies induced by varicella vaccine persist for atleast 20years
• cell mediated immunity is most important for VZV infections
• increases in varicella antibody may occur w HSV infections
Laboratory diagnosis for VZV
1.PCR - useful for sensitivity , specificity & rapidity
2.Isolation of VZV from vesicles in tissue culture : not sensitive
3.Serology : most frequently used are :
- FAMA(fluoroscent antibody to membrane antigen)
- ELISA
-Immuno adherant hemagglutination
Tzanck Smear – shows Cowdry type A, intranuclear inclusions; also antigen detection by PCR
Treatment of VZV
• y-Globulin of high VZV antibody titer can prevent development of illness in patients exposed to varicella who are at high risk of developing severe disease
-only effective if virus has not started
• Anti-viral drugs: acyclovir, valacyclovir , famciclovir , foscarnet
• Post herpetic neuralgia & acute neuritis
- analgesics,gabapentin , amitryptyline , lidocaine patch , glucocorticoid
• varicella - zoster immunoglobulin -for post exposure prophylaxis of high risk patients who lack serologic evidence of immunity
True or false? EBV is the most harmful herpesvirus
true
What are some properties of EBV
- genome
- no genes encoded
- strains of EBV
genome = 172kbp
• has G+C content of 59%
• Encodes 100 genes
2 major strains of EBV : type A & type B
What is the target cell of VZV
mucoepithelial cells of upper respiratory tract
Which receptor does EBV bind to & on which cell type
CD21 on b cell - and acts as Bcell mitogen
Explain pathogenesis of EBV
- Target : mucosal epithelium + B cells
- virus replicate in epithelium
- spread to waldeyers ring
- EBV bind to CD21 receptor ( also receptort for C3d component of complement system)
- Causes Bcell immortilization w retention of Bcell activity ( production of antibodies )
- Latent infection established in B cell - viral DNA incorporated into host DNA but remain inactive
- limited set of genes are exposed : some invariable some variable
Which genes are expressed by the EBV during latency
EBNA ,
EBER (Rna’s)
LMP ( latent membrane proteins )
Which viral gene of EBV is invariable and why ?
EBNA-1 - mainatins viral DNA in form of episomes ensuring virus genetic material remains stable in host
Which are the variable viral genes of EBV
EBNA-2,
EBNA 3
EBNA 3B
EBNA 3C
LP
How does EBV evade Immune system
- EBV- Bcell can still produce antibodies
- Downregulatio of MHC 1 on surface of infected cells thus avoid cytotoxic T cells
- EBNA-1
How can EBV affect memory b cell
- infects preexisting memory Bcells in memory Bcell resevoir
- Or infected EBV -bcells = differentiate to form infected memory B cells
Whats the immune response of EBV infection to Bcells
production of atypical reactive CD8+T cells (Downey cells - look like wine spill)
Downey cells may constitute up to 70% of WBC count
heterophile antibodies are produced to B cell mitogenesis
Reactivation of EBV
- Triggers such as : weakened immune system , stress , infections , hormonal changes
- activation of early genes (BZLF1 & BRLF1)
expressiion of lytics genes - viral replication
- the new virus particles are assembles & released from infected cell causing host cell to burst releasing virus particles into surrounding
- virus particles go on to infect other cells(like uninfected naive Bcells ) - spreading infection
Whats incubation period of EBV
4-6weeks
What are the 3 CLASSES of viral antigens of EBV
- Latent phase antigens - EBNA & LMP : EBNA1 is the only one invariably expressed : LMP1 mimics an acitvated growth factor receptor
- reveals EBV genome is present
2.early antigens = non structural proteins whose synthesis is not dependent on viral DNA replication
- production of these indicates onset of viral replication
3.Late antigens are the structural proteins ( capsid , envelope)
- are produced in cells undergoing productive viral infection
Epidemiology of VZV
• EBV occurs in all parts of world
• 90% of adults are seropositive
• Infection occurs early in life (>90% children are infected by 6 years ) = asymptomatic
• Primary infection in adults & adolescents tend to develop infectious mononucleosis
Clinical findings of EBV
- Infectious mononucleosis
2.Cancer
Types of cancer caused by EBV
- Burkitt lymphoma- jaw
- gastric carcinoma - stomach
- nasopharyngeal carcinoma - epithelial cells
-hodgkin & non-hodgkin lymphoma
What are major symptoms of infectious mononucelosis + duration of disease
SORE THROAT
ENLARGED LYMPH NODE ( posterior auricular cervical lymphadenopathy)
splenomegaly
FATIGUE
fever
malaise
headache
Self limited disease = lasts 2-3 weeks
Burkitt lymphoma
- type tumor?
- epidemiology?
- tumor of maxilla & mandible (abdomen in sporadic form)
- African children + young adult
- Malaria cofactor = foster enlargement of pool of EBV infected cells
Nasopharyngeal carcinoma
tumor of epithelial cells
predominately in asia ( chinese men )
What clinical presentations are associated with AID patients infected w EBV
- EBV associated lymphoma
- Oral hairy leukoplakia - epithelial focus of EBV replication
how is Hodgkin B Cell Lymphoma of Mixed Cellularity caused by EBV diagnosed
diagnosed with Reed-Sternberg cells that look like owl eyes
Laboratory diagnosis of EBV
- PCR assay
- nucleic acid hybridization
- Heterophile-antibody positive (IgM antibodies that recognize the Paul-Bunnell antigen on sheep and bovine RBCs)
- Mono-spot test for rapid diagnosis
- Serology
IgM to viral capsid antigen = indicates current infection
IgG to viral capsid antigen = Indicates past infection + immunity
What is the paul bunnel test
Bcell infected with EBV undergo polyclonal explainsion. The antibodies include IgM heterophile antibody
Agglutination of horse or sheep RBC by serum absorbed to exclude natural antibody is basis of this test
True or false is CMV the most common cause of congenital infection
TRUE
How is EBV spread
salivary secretions
blood transfusions
semen via sexual contact
organ transplantation
Where do EBV establish latency
Bcells
What is the target cell of EBV
mucoepithelial cells
Bcells
Properties of CMV
- largest genetic content ( 240kbp)
- replicates slowly in culture
- produces cytopathic effect and multinucleated cells can be seen
Treatment for EBV
- For uncomplicated Mono, treatment is symptomatic; if mistakenly given amoxicillin or ampicillin, can develop maculopapular rash
- avoid contact sports due to risk of splenic rupture
-ACyclovir = reduce EBV shedding from oropharynx
Pathogenesis of CMV
- enters through gential tract / upper respiratory tracts
- CMV infects the salivary glands epithelial cells
- virus spreads throuhg bloodstream to various organs & tissues
- establishes a persistent infection in fibroblasts, epithelial cells, and macrophages;
- latency is established in mononuclear leukocytes like B
and T cells and macrophages , myeloid progenitor cells
Where is latency established by CMV
monocytes & myeloid progenitor cells
How can reactivation of CMV occur
stress
immunodeficieny
immunosuppressive medication
cause viral genetic material to be trasncribed & translated leading to production of new virus particles
Whats the incubation period of CMV
4-8 weeks
How CMV affects normal host , immunosuppressed hosts , congenital & perinatal
normal host
• Virus causes systemic infection : lung , liver , oesophagus , colon , kidneys , monocytes , T & B lymphocytes
• cell mediated immunity is depressed w primary infection & may take several months for cellular responses to recover
Immunosuppressed host
- primary infection more severe
-Viral excretion is increased & prolonged
Congenital & perinatal infections
- its severe
• Babies have developmental defect & mental retardation
• Virus can be transmitted inutero(40%) w both primary & reactivated maternal infections
- acquired through delivery / breast milk
How is CMV spread
• How transmission happens: through close person - person contact
- urine , saliva , semen , breast milk , cervical secretions , blood transfusions
Disease caused by CMV in normal hosts
- infectious mononucleosis syndrome
- CMV causes 20-50% of heterophil - negative (non-EBV) mononucleosis
2.Subclinical hepatitis
3.Hepatosplenomegaly = in children younger than 7 years
Disease caused by CMV in immunosuppressed patients
1.pneumonia , colitis , retinitis / hepatitis /disseminated infection
2.Virus associated leukopenia = common in solid organ transplant
3. Obliterative bronchiolitis = seen in lung transplant
4.AIDS patients = CMV causes disseminated disease in untreated patients (CD4+ <50-100/ul)
- colitis & chorioretinitis (may cause blindness)
Disease caused by CMV in infants
- Cytomegalic inclusion disease
- isolated pneumonia & hepatitis
What two systems does cytomegalic inclusion disease involve
1.CNS
2. Reticuloendothelial system
Clinical features of cytomegalic inclusion disease
*jaundice
*hepatosplenomegaly
*thrombocutis purpura (blueberry muffin baby)
CNS disease
microcephaly
Intrauterine growth retardation
thrombocytopenia(low platelet levels )
Survivors : sensorineural hearing loss in children
Immunity to CMV
• antibodies to CMV in human sera increases with age (40% in teens to 80% in those more than 60yrs)
• Reactivation of latent infection occurs in presence of humoral immunity
• Presence of antibody in breast milk does not prevent transmission of infection to breastfeeding infants - they protect more againt devt serious disease rather than virus transmission
Laboratory diagnosis of CMv
- PCR
2.Monoclonal antibodies against viral antigens
3.Human fibroblast - used for virus isolation & cultured
-has small foci of swollen translucent cells w large intranuclear inclusions
owl eye inclusions seen on biopsy
4.resistance testing - sequence viral kinase & DNA polymerase
• UL97 Mutations = confer resistance to ganciclovir
• UL54 mutations = confer resistance to ganciclovir , cidofovir & foscarnet
Drugs that can be used for CMV infections
Ganciclovir ( nucleoside related to acyclovir)
Cidofovir (nucleoside polymerase inhibitor)
Foscarnet ( analog of inorganic pyrophosphate)
Acyclovir
Valacyclovir
Prophylatic ganciclovir
How/who does Ganciclovir work against CMV
- for immunosuppressed patients
-reduces severity of CMV retinits , esophagitis & colitis , disseminated CMV disease - controls progressive hearing loss in neonattes w congenital infect
How does Cidofovir & forscarnet work against CMV
- treat CMV retinitis & ganciclovir resitant CMV strains
Which patients is acyclovir & valacyclovir used for in CMV Infections
bone marroe & renal transplant patients
How does prophyaltic gangciclovir work against CMV infections
-for solid organ transplant ptnt - prevent devt of CMV disease - must be weighed againt the possibility for ganciclovir to cause leukopenia
how to control CMV infections
• isolation of newborn w cytomegalic inclusion disease from other newborns
• Screen transplant donor & recipients for CMV antibody to prevent transmissions
Where was the first HHV-6 isolated from
Blood of patients with AIDS grown in T cell cultures
How is HHV-6 spread
oral secretions: saliva
True or false ? HHV-6 has two variant A&B
TRUE
Properties of HHV-6
Viral DNA = 160-170kbp
has cross reactivity with HHV-7
Where does HHV-6 establish latency
CD4 T lymphocytes
Which receptor does HHV-6 bind to
CD46
What is the disease caused by both HHV-6 & HHV-7
Exanthem Subitum (ROSEOLA INFANTUM /SIXTH DISEASE)
Clinical presentation of Sixth disease
high temp fever for 3-5 days
can cause febrile seizure
after fever subsides
lacy body rash appears that SPARES FACE
Who is most likely affected by sixth disease
children (6months - 2yrs)
laboratory diagnosis of HHV-7
•PCR assay for viral DNA in saliva /blood test
• Seroepidemiologic studies using immunofluorescence tests for serum antibodies
True or false ? Are both HHV-6 & HHV-7 T-lymphotropic
TRUE
Where was the first HHV-7 isoated from ?
activated T cells recovered from peripheral blood lymphocyes of a healthy individual
Where do HHV-7 infections establish
salivary glands
Properties of HHV-8
Lymphotropic
genome= 156kbp
closely related to EBV & Herpes virus saimiri
Diseases caused by HHV-8
karposi sarcoma
vascular tumor
multicentric castleman disease
primary effusion lymphoma
How is HHV-8 spread
oral secretions , vertically ( blood /organ transplants),sexually
Clinical features of kaposi sarcoma
- erythematous(skin redness)
- violaceous lesions on nose , mucus membranes (of GI tract) but not common on hard palate
- lesions may be present as plaque, patch , macuole/nodule they arise from primitive vascular forming mescenchymal cells
What is primary effusion lymphoma caused by HHV-8
HHV-8 Infects Bcells as well which can cause B cell lymphoma
Epidemiology of HHV-8
common in africans
acquires early in life
Drugs that can be used to treat HHV-8
• Foscarnet , famciclovir , gangciclovir & cidofovir = work against KSHV replication
Laboratory diagnosis for HHV-8
• PCR assay
• Serologic assays - measure persisent antibody to KSHV by indirect immunofluorescence , western blot , enzyme linked immunosorbent assay format
