Lecture 18 - Herpesviruses

Question 1

Passive immune evasion strategies of persistent infections 1) 2) 3) 4)

Answer 1

1) Cell tropism is nonreplicating cells
2) Replicates in sites not exposed to the immune system (blood brain barrier, eye, luminal surface of ducts)
3) Replicates in MHC negative cells (such as neurons)
4) Can spread by cell-cell fusion

Question 2

Active immune evasion strategies of persistent infections 1) 2) 3) 4) 5) 6)

Answer 2

1) Limit expression of viral genes
2) Non-cytopathic infection (DNA genome integration)
3) Blockade of specific immune defences (block MHC, IFN, decoy cytokine receptors)
4) Blockade of apoptosis mechanisms
5) Rapid genetic evolution
6) Immunosuppressive, anergic epitopes

Question 3

Anergy

Answer 3

When an epitope doesn’t elicit an immune response

Question 4

Latent infection

Answer 4

Persisting infection with long periods without any detectable infectious virus or disease

Question 5

How many herpesviruses lead to latent infection?

Answer 5

All

Question 6

Breadth of species that can be infected by herpesviruses

Answer 6

Virtually all species

Question 7

Structure of herpesvirus virion 1) 2) 3) 4) 5)

Answer 7

1) gB, gN glycoproteins on envelope
2) Enveloped
3) Tegument
4) Nucleocapsid
5) Circular dsDNA genome

Question 8

Number of herpesviruses establishing life-long latency in humans

Answer 8

Eight

Question 9

Broad types of herpesviruses 1) 2) 3)

Answer 9

1) Alphaherpesviruses
2) Betaherpesviruses
3) Gammaherpesviruses

Question 10

Alphaherpesviruses 1) 2)

Answer 10

1) Herpes simplex (HSV-1 and
2) Oropharyngeal and genital infections
2) Varicella-zoster virus Chickenpox and shingles

Question 11

Betaherpesviruses 1) 2)

Answer 11

1) Cytomegalovirus Mild fever Pneumonia, chorioretinitis in immunocompromised patients
2) Human herpesvirus 6 (HHV-6) Mild rash in infants (roseola infantum)

Question 12

Gammaherpesviruses 1) 2)

Answer 12

1) Epstein-Barr virus Infectious mononucleosis Burkitt’s lymphoma Nasopharyngeal carcinoma Immunodeficiency-related lymphoproliferative disease
2) Kaposi sarcoma virus (HHV-8)

Question 13

Where are alphaherpesviruses persistent?

Answer 13

In neurons

Question 14

Where are betaherpesviruses persistent?

Answer 14

Maybe in monocytes or secretory glands

Question 15

Where are gammaherpesviruses persistent?

Answer 15

In lymphocytes

Question 16

Length of herpesvirus genomes

Answer 16

120-240kb

Question 17

Number of proteins that herpesviruses encode

Answer 17

Normally around 80 proteins

Question 18

Common early genes for herpesviruses

Answer 18

Enzymes (HSV thymidine kinase) and regulatory genes (HSV host shut-off gene product)

Question 19

What does HSV produce during latency?

Answer 19

Latency Associated Transcripts (LATs).

Question 20

What does EBV produce during latency?

Answer 20

EBNA 1-6 proteins

Question 21

HSV1 prevalence

Answer 21

70-90% adults seropositive

Question 22

HSV2 prevalence

Answer 22

20-60% adults seropositive

Question 23

CMV prevalence

Answer 23

40-100% prevalence

Question 24

EBV prevalence

Answer 24

90% adults seropositive

Question 25

How do herpesvirus genomes persist in cells?

Answer 25

As a circular, non-integrated DNA (episome)

Question 26

EBV genome origins of replication 1) 2)

Answer 26

1) Ori-P (Origin of plasmid maintenance) - Used to replicate genome during latent infection of dividing B cells 2) Ori-Lyt - Used to replicate genome during lytic infection

Question 27

Ori-P

Answer 27

EBV origin of plasmid maintenance. Used to replicate EBV genome during latent infection of dividing B cells. Binding site of EBNA-1 protein (a latent gene product).

Question 28

HSV genome origins of replication.

Answer 28

Has both Ori-P and Ori-Lyt, which are both inactive during latency, and both active during lytic infection.

Question 29

How do herpesviruses replicate their genomes?

Answer 29

Fork replication, rolling circle.

Question 30

Rolling circle replication

Answer 30

Question 31

How are concatemers formed during herpesvirus genome replication?

Answer 31

ssDNA from rolling replication has discontinous strand formed on it.

Question 32

EBV Ori-P driven infection

Answer 32

Latent replication in replicating B cells. Needs EBNA-a

Question 33

EBV Ori-L driven infection

Answer 33

Active, lytic infection

Question 34

Why doesn't HSV need to express latent proteins, as EBV does?

Answer 34

HSV lies latent in non-replicating cells (neurons). Therefore, the episome won't be diluted out with replication.

Question 35

Number of HSV infections that are asymptomatic

Answer 35

85-90%

Question 36

Number of HSV infections that result in lesions

Answer 36

10-15%

Question 37

Number of HSV infections that enter blood and distant organs (EG: brain)

Answer 37

Under 1%

Question 38

HSV CNS disease 1) 2) 3) 4)

Answer 38

1) Very rare (1-3000 cases per year) 2) Most common during disseminated infection of a newborn 3) 70% mortality rate. Under 2.5% achieve normal neurological function after infection. 4) Diagnosed by PCR of CSF, confirmed by viral culture.

Question 39

Where on the lip does HSV-1 normally recur?

Answer 39

Mucocutaneous junction

Question 40

Dorsal root ganglia that HSV will be latent in if initial infection is of the lip

Answer 40

Trigeminal ganglia

Question 41

Dorsal root ganglia that HSV will be latent in if initial infection is of the genitals

Answer 41

Sacral ganglia

Question 42

Size of HSV latent genome

Answer 42

150kb

Question 43

Number of people who harbour latent HSV genome

Answer 43

20%

Question 44

Number of HSV episomes per cell

Answer 44

10-100's

Question 45

Size of HSV LATs

Answer 45

~2kb

Question 46

Type of axonal transport used by re-emerging HSV

Answer 46

Anterograde transport

Question 47

LATs 1) 2) 3)

Answer 47

1) Stable, non-translated HSV RNA transcripts 2) ~2kb 3) Processed into viRNAs

Question 48

Potential role of LATs

Answer 48

Suppress apoptosis, to maintain latency

Question 49

How is primary viremia of VZV spread?

Answer 49

In DCs

Question 50

How is secondary viremia of VZV spread?

Answer 50

In T lymphocytes

Question 51

Timeline of VZV infection

Answer 51

Day 0 - Infection of conjunctiva and/or mucosa of URT - Viral replication in regional lymph nodes Day 4-6 - Primary viremia in bloodstream (DC spread) - Further viral replication in liver and spleen - Secondary viremia (T cell spread) Day 10 - Appearance of infectious vesicular rash

Question 52

Most effective response to herpesvirus infections

Answer 52

T cell response

Question 53

Where does VZV reemerge as shingles?

Answer 53

The dermatome where the virus initially infected

Question 54

How can shingles be treated?

Answer 54

Acyclovir or other antivirals. Passive VZV MABs

Question 55

Demographic at risk of shingles

Answer 55

Elderly (associated with immune decline). Children under 5 (from incomplete T cell immunity)

Question 56

Human VZV vaccine 1) 2) 3)

Answer 56

1) Live attenuated 2) Recommended for all seropositive children after 12 months of age, booster at 10 years 3) Recommended for those at risk - teachers, health care workers

Question 57

How is EBV transmitted?

Answer 57

Direct contact with infected saliva with oropharynx

Question 58

Where does EBV-1 predominate?

Answer 58

Australia, Europe, USA

Question 59

Where is EBV-2 found?

Answer 59

EBV-1 and -2 are equally prevalent in Africa

Question 60

Where does EBV establish a productive infection?

Answer 60

Epithelial cells of the salivary glands and oropharynx

Question 61

Site of EBV latency

Answer 61

B cells

Question 62

What might EBV cause in transplant recipients?

Answer 62

B-lymphoproliferative disease

Question 63

Is EBV initial infection lytic?

Answer 63

Yes

Question 64

Does primary EBV cause a large immune response?

Answer 64

Yes

Question 65

EBV proteins expressed during latency 1) 2)

Answer 65

1) Epstein-Barr virus Nuclear Antigens (EBNA). 6 Of these proteins. 2) Latent membrane proteins (LMP). 2 of these.

Question 66

Protein involved in replication of EBV genome

Answer 66

EBNA-1

Question 67

Three types of EBV latency

Answer 67

1) 9 latent antigens expressed 2) 3 latent antigens expressed 3) Only EBNA-1 expressed during latency

Question 68

Disease associated with type 1 EBV latency

Answer 68

B-lymphoproliferative disease

Question 69

Disease associated with type 2 EBV latency

Answer 69

Hodgkins disease

Question 70

Disease associated with type 3 EBV latency

Answer 70

Burkitts lymphoma

Question 71

Type of EBV mRNA that 90% of adults have in B cells

Answer 71

EBV LMP2a mRNA present in memory B cells

Question 72

Malignancies associated with EBV reactivation

Answer 72

Hodgkins lymphoma, Burkitts lumphoma, nasopharyngeal carcinoma

Question 73

What can congenital CMV infection lead to?

Answer 73

Deafness, chorioretinitis, microencephaly

Question 74

Leading infectious cause of stillbirth

Answer 74

CMV

Question 75

How does CMV infect a foetus?

Answer 75

~30% chance of crossing placenta form mother to foetus