Iahi: 3.07 - Herpesviruses

Front 1

What is the genome / structure of Herpesviruses?

Back 1

- dsDNA linear
- Enveloped
- Tegument

Front 2

What are the three subfamilies of Herpesviruses?

Back 2

- α - Herpes Simplex Virus (HSV-1 and -2); Varicella Zoster Virus (VZV = HHV-3)
- β - Cytomegalovirus (CMV = HHV-5), Roseolovirus (HHV-6), HHV-7
- γ - Epstein-Barr Virus (EBV = HHV-4), Kaposi's Sarcoma Virus (KSHV = HHV-8)

Front 3

What are the α-Herpesviruses?

Back 3

HHV-1, -2, -3:
- Herpes Simplex Virus (HSV-1 and HSV-2)
- Varicella Zoster Virus (VZV = HHV-3)

Front 4

What are the β-Herpesviruses?

Back 4

HHV-5, -6, -7:
- Cytomegalovirus (CMV = HHV-5)
- Roseolovirus (HHV-6)
- HHV-7 (less common cause of roseola)

Front 5

What are the γ-Herpesviruses?

Back 5

HHV-4, -8:
- Epstein-Barr Virus (EBV = HHV-4)
- Kaposi's Sarcoma Virus (KSHV = HHV-8)

Front 6

What makes a virus a Herpesvirus?

Back 6

- Encode collection of enzymes involved in nucleotide metabolism (thymidine kinase), DNA synthesis (DNA polymerase), and protein kinase
- Synthesis of viral DNA and capsid assembly in nucleus; the rest of the virion assembled in cytoplasm
- Two life-cycles: lytic and latency

Front 7

What is the purpose of viral vhs protein?

Back 7

Protein of Herpesvirus
- Virion host shut-off
- Degrades host mRNA

Front 8

What transcription factor initials herpesvirus gene transcription?

Back 8

VP16 --> localizes to nucleus

Front 9

What happens during the latent stage of Herpesvirus?

Back 9

- Immune system clears replicating virus during acute infection
- HSV maintains latency w/ occasional reactivation for life of host
- Same strain persists within same host as an episome (associated w/ host neucleosomes)
- Very little if any gene expression (repression of lytic genes)

Front 10

What can re-trigger a latent Herpesvirus infection?

Back 10

- Immunocompromise
- Stress
- Infections w/ other viruses
- UV irradiation
- Physical trauma (damage of neurons)

Front 11

What are the differences in incidence of HSV-1 vs HSV-2?

Back 11

- Majority of U.S. adults positive for HSV-1
- 17% positive for HSV-2 (25% of females, 12.5% of males)

Front 12

How are HSV-1 and HSV-2 transmitted?

Back 12

- HSV-1: respiratory secretions, saliva (more common from oral cavity)
- HSV-2: sexual contact, perinatal (more common from genital tract)

Front 13

How do HSV-1 and HSV-2 infect sensory neurons? Where?

Back 13

- After primary infection there is robust replication
- May disseminate via retrograde transport to sensory ganglia where it maintains latency
- HSV-1 --> trigeminal ganglia
- HSV-2 --> sacral ganglia

Front 14

How is HSV latency characterized?

Back 14

- Expression of a group of viral mRNAs called Latency Associated Transcripts (LATs) - never translated into protein
- Function to repress HSV gene expression (unknown mechanism)
- Unknown stimuli trigger viral reactivation

Front 15

What are the chances of reactivation of untreated HSV-2?

Back 15

25% on any given day

Front 16

What is meant by an exogenous re-infection?

Back 16

Reinfection of a seropositive individual with a different strain of HSV (possible but uncommon)

Front 17

How do you treat Herpesvirus (HSV-1 and HSV-2)?

Back 17

- Target replicating virus only
- No way to clear latent herpesvirus infections
** Tx of choice: Nucleoside analogs (Acyclovir) - inhibits viral but not cellular DNA synthesis
- Relies on immune system to clear cells that lytically replicate herpes

Front 18

What is the mechanism of Acyclovir?

Back 18

- Suicide inhibitor - competes w/ dGTP for VIRAL DNA polymerase
- Binds to Acyclovir irreversibly
- Does not affect cellular DNA polymerase

Front 19

What are the symptoms of HSV-1 infection?

Back 19

* Acute Herpetic Gingivostomatitis or Pharyngitis
* Herpes Labialis (cold sore)
* Keratoconjunctivitis (leading cause of blindness)
* Temporal lobe encephalitis
- Herpes gladiatorium (dermatitis in athletes - wrestling)
- Herpes whitlow (hand dermatitis - esp. health care workers - gloves don't prevent transmission)
- Some genital lesions
- Neonatal herpes
- Latent in trigeminal ganglia

Front 20

What are the symptoms of HSV-2 infection?

Back 20

* Herpes genitalis
* Neonatal herpes
- Some oral lesions
- Latent in sacral ganglia

Front 21

What are the characteristics of Neonatal Herpes?

Back 21

- Can be caused by both HSV-1 and HSV-2
- Inoculation during birth (most common) but also during pregnancy (birth defects)
- Infxn during 1st tri --> miscarriage, infxn during 2nd or 3rd tri --> birth defects
- Replicating in CNS
- Disease usually manifests within days of life (may not have skin lesions though - hard to diagnose)
- High mortality - even w/ Acyclovir
- Neurological abnormalities in survivors

Front 22

How do you diagnose Herpesvirus (HSV-1 and HSV-2)?

Back 22

- Vesicles at site of inoculation
- Culture of virus, immunofluorescence w/ antibodies against HSV antigens, PCR assays
- Serology

Front 23

What is the causative agent of Chickenpox? How long does it incubate?

Back 23

- Varicella Zoster Virus (VZV = HHV-3)
- 10-21 days

Front 24

How is Varicella Zoster Virus (VZV = HHV-3) spread?

Back 24

- Person-to-person contact
- Infectious even before skin lesions appear
- Aerosolized both from lesions and from respiratory tract

Front 25

Where does Varicella Zoster Virus (VZV = HHV-3) replicate?

Back 25

- T cells
- Epithelial cells
- Endothelial cells
- Latency in sensory nerve ganglia (dorsal root and/or trigeminal ganglia)

Front 26

How does Varicella Zoster Virus (VZV = HHV-3) latency differ from HSV-1 and HSV-2 latency?

Back 26

In VZV, several viral gene products are actively transcribed and translated within latently infected neurons

Front 27

What are the symptoms of Varicella Zoster Virus (VZV = HHV-3) --> Chickenpox?

Back 27

- Blisters (50-300)
- Itching
- Malaise
- Fever
- Secondary bacterial infection may occur in blisters
- Secondary skin infection and pneumonia more common if primary infection during adulthood
- Can be fatal in immunocompromised patients

Front 28

How is Varicella Zoster Virus (VZV = HHV-3) infection (chickenpox or shingles) treated?

Back 28

Antivirals (acyclovir, VZV immune globulin)

Front 29

What causes Herpes Zoster?

Back 29

- Shingles
- Varicella Zoster Virus (VZV = HHV-3) reactivation of latent infection

Front 30

What are the symptoms of Varicella Zoster Virus (VZV = HHV-3) --> Shingles / Herpes Zoster?

Back 30

- Reactivation of a single (usually) sensory ganglia --> shows up in single dermatome
- >50 yo
- If in Trigeminal ganglia --> vision impairment
- Complication: postherpetic neuralgia

Front 31

What causes Postherpetic Neuralgia? Symptoms?

Back 31

- Significant complication of Herpes Zoster (Varicella Zoster Virus (VZV = HHV-3))
- Severe pain at dermatome w/o vesicular lesion
- Can mimic appendicitis or a heart attack
- Lasts for many months
* Antivirals have no effect

Front 32

What are important differential diagnoses for Varicella Zoster Virus?

Back 32

- Bacterial or enterovirus infections
- Contact dermatitis
- Disseminated HSV
- Historically, smallpox

Front 33

What are the characteristics of the Varicella Zoster Virus (VZV = HHV-3) vaccine? Efficacy?

Back 33

- Live-attenuated virus - Oka strain
- Given to young children (2 doses)
- 15-20% will get infected w/ wild-type VZV --> establishes latency
- Reduces severity of primary infection
- Can reactivate and cause Zoster / Shingles (milder symptoms)
- Can be transmitted to immunocompromised (be careful if there are immunocompromised siblings)
- Used in elderly to prevent Zoster / Shingles (>60 yo)

Front 34

What are the β-Herpesviruses?

Back 34

HHV-5, -6, -7:
- Cytomegalovirus (CMV = HHV-5)
- Roseolovirus (HHV-6)
- HHV-7 (less common cause of roseola)

Front 35

What are the γ-Herpesviruses?

Back 35

HHV-4, -8:
- Epstein-Barr Virus (EBV = HHV-4)
- Kaposi's Sarcoma Virus (KSHV = HHV-8)

Front 36

What does "Lymphotropic" Herpesvirus mean?

Back 36

- Replication in cells including lymphoid origin
- β - CMV (HHV-5) --> Monocytes and Macrophages
- β - Roseolovirus (HHV-6) --> T-lymphocytes
- γ - EBV (-4) and Kaposi's Sarcoma Virus (KSV, -8) --> B lymphocytes and plasma cells

Front 37

What type of virus is Cytomegalovirus (CMV)? What cells does it replicate in? What do the infected cells look like?

Back 37

- Herpesvirus (HHV-5)
- Replicates in monocytes and macrophages
- Infected cells look like "owl eyes", inclusion bodies

Front 38

Who is infected with Cytomegalovirus (CMV) (HHV-5)?

Back 38

Associated with socio-economic condition and age:
- 40-80% in US
- ≥ 90% in developing countries

Front 39

What are the symptoms of Cytomegalovirus (CMV) (HHV-5) in healthy adults?

Back 39

- Mild mononucleosis
- Cold-like symptoms

Front 40

What is the leading cause of congenital birth defects? Symptoms?

Back 40

- Cytomegalovirus (CMV) (HHV-5)
- Mild-to-severe retardation
- Deafness and vision loss (permanent)
- Death
- Petechial lesions, small size, hepatosplenomegaly, jaundice
- Seizures

Front 41

What are the long-term persistent infection associations of Cytomegalovirus (CMV) (HHV-5)?

Back 41

- Atherosclerosis
- Immunosenescence

Front 42

What is the genome / structure of Cytomegalovirus (CMV) (HHV-5)?

Back 42

- dsDNA (linear)
- Icosahedral
- Tegument and envelope

Front 43

How is Cytomegalovirus (CMV) (HHV-5) transmitted?

Back 43

Direct contact w/ virus-containing secretions:
- Sexual contact (semen, cervical secretions)
- Blood (transfusion), organ transplant
- Saliva, tears
- Brast milk
- Urine, feces
Inoculation onto a mucosal site

Front 44

Where is Cytomegalovirus (CMV) (HHV-5) most commonly transmitted?

Back 44

Daycares

Front 45

What is the immune response to Cytomegalovirus (CMV) (HHV-5)?

Back 45

- Innate: macrophages, interferon, NK cells (control but insufficient to clear)
- Humoral: limits re-infection or reactivation
- CMI: cytotoxic T cells kill CMV-infected cells (up to 10% of all CD8 T cells may be directed against CMV)
- Unable to completely control CMV; re-infection does occur

Front 46

What are the symptoms of Cytomegalovirus (CMV) (HHV-5) in healthy adults and children?

Back 46

- Mild but often unapparent
- Fever, fatigue, sore throat, headache (2-3 weeks)
- Subclinical hepatitis
- Lymphocytosis - increase number of lymphocytes and atypical lymphocytes
- Mononucleosis

Front 47

What causes 8% of all infectious mononucleoses?

Back 47

Cytomegalovirus (CMV) (HHV-5)

Front 48

What is the diagnosis if there are "Owl's Eyes" cells in urine or other tissues?

Back 48

Cytomegalovirus (CMV) (HHV-5)

Front 49

How do you treat Cytomegalovirus (CMV) (HHV-5) infection?

Back 49

- Ganciclovir (IV) or Valganciclovir (oral) - nucleoside analog, activ. by phosphorylation (inhibits DNA pol)
- Foscarnet (IV) - pyrophosphate analog (inhibits DNA pol)
- Cidofovir (IV) - nucleoside analog (inhibits DNA pol)
** Acyclovir is ineffective **
- Anti-CMV IgG (Cytogram) also given in conjunction

Front 50

How does Cytomegalovirus (CMV) (HHV-5) infection affect immunosuppressed?

Back 50

- Life threatening
* Pneumonia
* Retinitis
- Fever, hepatitis, encephalitis, myelitis, colitis, uveitis, and neuropathy

Front 51

What kind of virus is Epstein-Barr Virus?

Back 51

- γ-Herpesvirus (dsDNA)
- HHV-4

Front 52

What are the sites of infection with Epstein-Barr Virus (HHV-4)?

Back 52

- Replicate in B cells or epithelial cells (of pharynx)
- Latent infection in memory B cells
- Stimulates and immortalizes B cells

Front 53

How is Epstein-Barr Virus (HHV-4) transmitted?

Back 53

- Saliva (kissing disease)
- Blood
- Respiratory secretions

Front 54

What is the difference between Latency Type I/II and Type III for Epstein-Barr Virus (HHV-4)?

Back 54

- Type I/II - viral antigens in memory B cells; leads to Burkitt's, Hodgkin lymphomas, nasopharyngeal carcinoma
- Type III - viral antigens in proliferating B cells; infectious mononucleosis

Front 55

What causes mononucleosis in Epstein-Barr Virus (HHV-4)?

Back 55

Rapid proliferation of atypical T cells (Downey Cells) - overactive immune response

Front 56

When is Epstein-Barr Virus (HHV-4) infection most common? Symptoms?

Back 56

- Puberty - 25 years old (Kissing Disease)
- 5-20% of B cells infected w/ EBV in 1st week
- Fever, malaise, lymphadenopathy, exudative pharyngitis
* Splenomegaly (1-4 weeks)
- Due to T cell response
- Asymptomatic in young children

Front 57

What causes Post-Transplant Lympho-Proliferative Disorder (PTLD)? Incidence/prognosis?

Back 57

- Epstein-Barr Virus (HHV-4) mediated B cell proliferative disease
- Immunosuppressive therapy activates infection
- 1-33% transplants depending on organ w/in 1st year after transplant
- Arises in donor B cells or reactivation in recipient
- Low risk if graft contains donor T cells
- Poor prognosis: 40-70% mortality

Front 58

How can you treat Post-Transplant Lympho-Proliferative Disorder (PTLD) (due to reactivation of EBV)?

Back 58

- No antiviral drugs or vaccines
- Reduce immunosuppression (which is activating latent EBV)
- Make EBV-specific T cell lines from donor and infuse them

Front 59

How can you diagnose Epstein-Barr Virus (HHV-4) besides serology, fluorescence, and PCR?

Back 59

- Test for heterophile antibodies by agglutination of animal RBCs
* Monospot test (horse RBC) = +

Front 60

What cancers are associated with Epstein-Barr Virus (HHV-4)?

Back 60

- Burkitt's Lymphoma (B cell lymphoma of jaw and face, in children 5-10 yo; associated w/ chromosomal translocation)
- Hodgkin's Lymphoma
- Nasopharyngeal epithelial carcinoma

Front 61

Which Herpesvirus is a common cause of admittance to ER for infants? Symptoms? Where does it replicate?

Back 61

- HHV-6b (β-herpesvirus)
- dsDNA
- High fever ~ 4 days, irritability, malaise, lymphadenopathy, rash (ROSEOLA)
- Replicates in CD4+ T cells

Front 62

What cancers are associated with HHV-8? Where does it replicate?

Back 62

- Kaposi's Sarcoma (γ-Herpesvirus)
- Replicates in CD19+ peripheral B cells, endothelial cells, monocytes, keratinocytes, and epithelial cells

Front 63

What kind of humoral immunity is used against a primary EBV infection?

Back 63

Heterophile antibodies

Front 64

T/F: CMV infection can be detected by PCR and treated w/ Acyclovir?

Back 64

False - acyclovir is ineffective for CMV

Front 65

What virus causes PTLD (Post-Transplant Lympho-Proliferative Disorder)?

Back 65

EBV - Epstein-Barr Virus (HHV-4)

Front 66

Where is Cytomegalovirus (CMV) frequently contracted from?

Back 66

Daycares

Front 67

What viruses cause infectious mononucleosis?

Back 67

- EBV
- CMV

Front 68

what is the causative agent for chickenpox/shingles?

Back 68

varicella-zoster

Front 69

should you use aspirin to treat varicella zoster

Back 69

no, it is counter indicative as it predisposes kids to liver damage [reyes syndrome]

Front 70

what does the vaccine Virus-Oka treat and how is it administered? how does it work?

Back 70

for varicella zoster: two doses Establishes a latent infection that has a mild re-emergence later in life compared to a wild strain.