CMV, EBV, KSHV (HHV-8)

Question 1

What type of virus are CMV, EBV, and KSHV?
• What do they share a common tropism for?
• Which of these cause cancer?

Answer 1

All are herpes Viruses

• All share tropism for Lymphocytes
• EBV and KSHV are oncogenic

Question 2

Describe the following structural features of the Herpes virus? 
• Genome Structure
• Capsid style
• Enveloped
• Where does virus assembly take place?

Answer 2

Genome:
• Linear dsDNA (150-250 kbp)

Capsid:
• Icosahedral Capsid
• Enveloped

REPLICATION AND ASSEMBLY TAKE PLACE INSIDE THE HOST CELL NUCLEUS

Question 3

Which of the herpes viruses is the largest?

Answer 3

CMV is the largest

Question 4

What is the Tegument?

• what is found here?

Answer 4

Tegument:
• Found Between the envelope and capsid

What does it contain:
•number of proteins needed to infect the cell and shut down host cell synthesis of normal proteins to produce viral proteins

Question 5

Which of the following are Beta and which are Gamma herpes viruses?

Answer 5

Beta = CMV

Gamma = EBV, HHV-8 (KSHV)

**Note: EBV and HHV-8 can cause cancers

Question 6

What is unique about the structure of the herpes virus linear genome structure for:
• CMV
• EBV

Answer 6

• Line is divided into Long Segement and Short segment

CMV:
• Flanking each of these segments is two pairs of genes that are the same but run in opposite directions

EBC:
• Internal Repeats separate Long and short segment

Question 7

T or F: herpes viruses can take part in a lytic cycle OR stay in a latent phase.

Answer 7

TRUE, the latent phase is what makes herpes life-long

Question 8

Describe the Steps in the Lytic Cycle for Herpes viruses.

Answer 8

ENVELOPE fuses with cell and NUCLEOCAPSID rides microtubules to host nuc.

Immediate Early Phase
• Early Transciption Factors - redirect host RNA pols. to make viral genes

Early Phase
• HERPES own DNA pols replicates Genome

Late Phase
• Packing into capsid occurs in the nucleus

Assembled Virus Buds from the Nucleus and out of the cell

Question 9

What events occur if the herpes virus decides to undergo a latent phase rather than lytic?

Answer 9

• NO VIRAL PARTICLES are PRODUCED
• Entire Genome is Maintained Extrachromosomally
• FEW viral genes are expressed

Question 10

What are the 3 phases of latency?

• What causes the final stage?

Answer 10

Establishment

Maintenance

Reactivation - Due to a Loss in Host Immune Response

Question 11

T or F: latency in herpes viruses causes the infection to be LIFE-LONG

Answer 11

True

Question 12

What 4 drugs are most often used to treat Herpes viruses?

• Which are 1st line and which are 2nd line?

Answer 12

4 Drugs:
1st line (pro-drugs)
• Acyclovir
• Ganciclovir

2nd line (not pro-drugs) 
• Foscarnet
• Cidofovir

Question 13

Acyclovir

MOA

Answer 13

• PRODRUG is phosphorylated FIRST by HERPES Thymidine Kinase (two more phosphorylations occur by host kinases)
• Is Preferentially used by HERPES DNA pols.

(thymidine analogue)

Question 14

Which of the herpes drugs is most often used to treat CMV infections?

Answer 14

Ganciclovir

Question 15

Foscarnet

MOA

Answer 15

• Blocks Pyrophosphate Release (aka cleaving of the P-P bond)
• NOT a prodrug and DOES NOT REQUIRE activation

Question 16

Cidofovir

MOA

Answer 16

Cytidine analogue (doesn’t need to be activated)

Question 17

Why can’t anti-herpetic drugs cure herpes?

Answer 17

They ONLY affect herpes in its active Relicating state and have no effect on the lytic state

Question 18

T or F: CMV is not highly contagious , that’s why rates of CMV infection are generally very low in society.

Answer 18

FALSE, while it IS true that CMV is not highly infectious is it however VERY PREVALENT with 50-80% of adults being affected.

Question 19

T or F: Like HSV-1 both CMV and EBV are sexually transmitted.

Answer 19

False, CMV IS sexually transmitted while EBV is NOT (despite its reputation)

Question 20

What is the PRIMARY (first) site of replication for CMV?
• Secondary?
• Latency?

Answer 20

Primary:
Epithelial Cells

Secondary:
• Spreads through Lymphoid Tissue

Latency:
• Hangs out in B and T cells and Monocytes

Question 21

Compare and contrast Childhood infections of CMV with those that occur as an adult?

Answer 21

Childhood:
• Mostly Asymptomatic

Adulthood:
• can result in mononucleosis with fever

Question 22

How does CMV affect Neonates?

• How many are affected in utero?

Answer 22

• In utero CMV in 1% of U.S. births

* Asymptomatic 90% of the time but CAN cause Deafness and Mental Retardation

Question 23

What groups of people are at the highest risk of getting CMV infection?

Answer 23

• Immunocompromised (TRANSPLANT patients)
• Day Care Workers
• Pregnant Workers
• Gay Men

Question 24

When you think transplant patient, think CMV!

Answer 24

When you think transplant patient, think CMV!

Question 25

T or F: most transplant patients will develop a CMV infection.

Answer 25

True, but not all will cause disease

Question 26

How does CMV exposure occur in transplant patients? | • How would you treat someone who is at high risk for CMV exposure during transplant?

Answer 26

* CMV+ organ is recieved OR * REACTIVATION of latent CMV in CMV+ pt. • HIGH RISK (seropositive) pts. are given PROphylactic Ganciclovir and CMV Ig

Question 27

How do you diagnose and treat someone with a CMV infection? | • 1st and 2nd line treatment

Answer 27

Dx: • Detection of VERY Large Lymphocytes • ELISA, PCR, Shell Vial Assay Treatment: 1st line • Ganciclovir 2nd line • Foscarnet • Cidofovir

Question 28

What is a shell vial assay?

Answer 28

• Uses Antibody to detect Immediate Early Proteins | this is quicker because you don't have to wait for the virus to completely replicate

Question 29

What two cancers can be caused by EBV?

Answer 29

* Burkitt's Lymphoma | * Nasopharyngeal Carcinoma

Question 30

Which causes hairy leukoplakia of the tongue: EBV or CMV?

Answer 30

EBV

Question 31

Where is the primary site of replication for EBV? • Secondary? • Tertiary?

Answer 31

Primary - Epithelium Secondary - Lymph Nodes Tertiary - Liver and Spleen

Question 32

Why do people often not know they are infected with EBV and thus spread it to other people?

Answer 32

EBV remains latent in throat epithelia and B cells and there can be oral shedding for weeks

Question 33

What some of the key symptoms of Infectious Mononucleosis (EBV) infection?

Answer 33

* Sore Throat * Fever 1-2 wks * Malaise * Lymphadenopathy * Uneventful Recovery

Question 34

What patients present with hairy leukoplakia? | • what causes it?

Answer 34

AIDS patients are really the only people this is seen in • Caused by EBV

Question 35

How is EBV typically diagnosed?

Answer 35

* Symptoms * Greater than 50% atypical, LARGE lymphocytes * Monospot test (specific but not sensitive) * EBNA and VCA antigens

Question 36

How does the monospot test work? | • How good is this test at catching EBV?

Answer 36

HETEROPHILE antibodies agglutinate Sheep RBCs • on 1/2 of people infected with EBV ever produce ant-sheep antibody

Question 37

*What are EBNA and VCA?

Answer 37

EBNA (EB Nuclear Antigens) • Immediate Early proteins that Assist in transcription and Genome Replication VCA (Virus Capsid Antigen) • Produced during Lytic Replication

Question 38

*How are EBNA and VCA used to stage an EBV infection?

Answer 38

Anti-VCA rises before anti-EBNA therefore Primary Infection • Anti-VCA+ and anti-EBNA - Prior Infection • Anti-VCA+ and anti-EBNA+

Question 39

*What is posttransplant lymphoproliferative disease (PTLD)? • which transplant pts. are at highest risk? • What virus causes this? • How do we treat?

Answer 39

PTLD • B Cell lymphoma in Transplant Patients Highest Risk: • Patients in the 1st year of treatment who are SERONEGATIVE for EBV Treatment: • Stop Immunosuppression

Question 40

*Who typically gets Burkitt's lymphoma? | • factors that play a role in getting the disease?

Answer 40

Young Children in Central Africa Factors: • Early EBV infection - causes immortalization leading to more replication and more mutations * c-MYC gets activated as a result of mutations * Superimposed Malaria infection suppresses normal immune response to EBV

Question 41

How curable is Burkitt's lymphoma?

Answer 41

80% cure rate in cases that are detected early

Question 42

Which is more closely associated with EBV, Nasopharyngeal Carcinoma or Burkitts Lymphoma?

Answer 42

There is almost 100% association of Nasopharyngeal Carcinoma with EBV.

Question 43

Where is nasopharyngeal carcinoma most prevalent?

Answer 43

Southern China - thought to be tied in to high consumption of Nitrosamines and Grilled Fish in these areas

Question 44

``` Compare and Constrast EBV to CMV in terms of: • Cell in which it remains Latent • Effect on Transplant Patients • Transmission • Mono-spot test • Oncogenesis ```

Answer 44

Latency: • Occurs in B cells for Both Effect on Transplant Patients: • CMV - PNEUMONIA 1-4 months After transplant • EBV - B cell lymphoma Transmission: Both transmit through fluids (enveloped virus) • CMV - sexually transmitted • EBV - only transmitted via Saliva Monospot: • CMV - ALWAYS negativ • EBV - sometimes positive Oncogenesis: • only EBV causes cancer

Question 45

What are some diseases caused by HHV-8 (KSHV)?

Answer 45

* Kaposi's Sarcoma * Primary Effusion Lymphoma * Castleman's disease