Herpesvirus

Question 1

How many human herpesviruses are there?

Answer 1

8

Question 2

What is the structure of herpesvirus?

Answer 2

dsDNA 100-250kb genome 
proteinaceous core 
icosahedral capsid 
tegument
enevelope w glycoproteins

Question 3

what are he 2 life cycles of herpes virus?

Answer 3

lytic - produce virions

latent - persist in host

Question 4

what are the 3 subfamilies of herpesvirus?

Answer 4

Alphaherpesvirinae - HSV1/2
Beta”” HHV6/7, CMV
Gamma”” KSHV, EBV

Question 5

What are characteristics of the alphaherpesvirinae?

Answer 5

Variable host range
spread rapidly
latency - SENSORY GANGLIA

Question 6

What are characteristics of betaherpesvirinae?

Answer 6

Restricted host range
slow cell-cell spread
latency - LYMPHORETICULAR CELLS

Question 7

What are characteristics of gammaherpesvirinae?

Answer 7

Very restricted host range
Replicate - lymphoblastoid cells
latency - T/B CELLS

Question 8

How is the HSV genome organised?

Answer 8

encodes 80 gene products

2 covalently linked segments - flanked by inverted repeats

Question 9

What happens during HSV lytic cycle?

Answer 9

replicates in epithelial cells - in nucleus
infectious particle production & cell destruction
lytic burst = coldsore

Question 10

What happens to HSV during latent cycle?

Answer 10

Reversible non productive infection of a neuron
can be lifelong state
must evade immune response

Question 11

HSV lytic REPLICATION cycle?

Answer 11

attachment/penetration
transcription - IE, DE, late gene expression
Genome replication 
Virus assembly 
Virus envelopment & release

Question 12

What does virus entry of HSV require?

Answer 12

interaction between virus glycoproteins & cellular receptors
gB, gC bind
gD stabilises by binding to entry mediators

Question 13

How does HSV penetrate the host cell?

Answer 13

pH-independent fusion of viral envelope with plasma membrane
transport to NPC by microtubules

Question 14

How are HSV lytic genes expressed?

Answer 14

temporal cascae
IE - switch on expression of viral genes
E - enzymes for DNA replication
L - structural genes

Question 15

How is expression of IE initiated?

Answer 15

recruitment of cellular factors to IE promoters

tegument protein VP16/ alphaTIF enhances expression - interacts with transcription factors

Question 16

What are the roles of the IE proteins?

Answer 16

ICP0 - promiscuous transactivator, disrupts cellular ND10,
ICP27 - transactivates late genes, acts at posttranscriptional level
ICP4
ICP47

Question 17

How are PML bodies disrupted to help virus replication?

Answer 17

contain several cellular proteins
utilise PML bodies to enhance virus replication
also disrupt interferon-induced innate immune response

Question 18

What are the 7 viral genes essential for genome replication?

Answer 18

UL9
ICP8
UL5/8/52
UL30/42

Question 19

What are the early steps of HSV-1 genome replication?

Answer 19

UL9 - binds to 1 of 3 ORI after circularisation

UL9 + ICP8 cause bend in DNA = stem loop & unbinding

Helicase/primase complex (UL5/8/52) - bind ssDNA + makes RNA primers

viral polymerase UL30/42 binds RNA primers - synthesises DNA

Question 20

What is the rolling circle mechanism?

Answer 20

circular replication structure is nicked - rolling circle intermediate

forms concatemeric strands of viral progeny DNA

Question 21

What acts as the ATP-dependent pump that drives DNA into the procapsid?

Answer 21

terminase proteins (UL15, UL28, UL33)
they cut concatemeric DNA at specific sites

Question 22

How do the virus capsids exit from nucleus?

Answer 22

budding at inner nuclear membrane - enveloped primary virions in the perinuclear cleft

primary envelope fuse w outer nuclear membrane

Question 23

What is involved in HSV virion maturation?

Answer 23

capsids associate w tegument proteins

final envelopment - bud into golgi-derived exocytotic vesicles

Question 24

How do herpesviruses persistently infect the host via lifelong latent infection?

Answer 24

virus enters sensory neuronal axons and migrate to the cell body in a neuronal ganglion in the CNS

illness & stress - produce signal back down neuronal axon - latent infection will reactivate

Question 25

Why does HSV go latent in neurons?

Answer 25

tegument layer containing VP16 and HCF-1 is removed and remains in neuron cytoplasm = NO ACTIVATION of IE lytic gene expression

Question 26

Why can the adaptive immune system not clear the latently infected neurones?

Answer 26

CNS has limited responses to inflammatory cytokines e.g. IFNs neurones cannot be replaced - not easily cleared by immune cells

Question 27

What is the role of LAT?

Answer 27

virus is transcriptionally silent apart from expression of LAT LAT keeps genome silent & helps avoid host immune surveillance and apoptosis express 4 miRNAs - limit cytotoxic effects of lytic viral protein expression

Question 28

How does HSV reactivate from latency?

Answer 28

latent episome must reorganise chromatin & ensure levels of IE expression are sufficient to overcome miRNAs stimuli - HCF-1 & VP16 accumulation

Question 29

What is HSV1?

Answer 29

common cold sore virus herpes encephalitis - edema, hemorrhages 3.7Bn people have it

Question 30

What is HSV2?

Answer 30

genital herpes due to HSV-1 infection

Question 31

What happens to HSV-2 in neonates?

Answer 31

Outbreak of HSV2 when pregnant | newborn - weakened immune system = dramatic infection & severe neurological disease

Question 32

What is VSV?

Answer 32

Chicken pox shingles much more aggressive in elderly severe pain, damage to nerve endings in skin

Question 33

What is EBV?

Answer 33

linked to Burkitt's lymphoma & Hodgkin's disease more aggressive in the immunosuppressed

Question 34

How are herpesvirus infections controlled?

Answer 34

Vaccines Antivirals - Acyclovir New drugs - peptide blockers Novel - block cellular interactions

Question 35

How does Acyclovir and other nucleoside analogues act?

Answer 35

guanosine analogue activated by kinase only encoded by the virus - viral thymidine kinase forms ACV-MonoP further activated by cellular kinase into a triphosphate acts like nucleotide - competes with G Stops DNA replication - no ribose at end to add next base - chain terminated

Question 36

How do the new drugs Helicase-primase inhibitors act?

Answer 36

multiple enzyme activities enhancing the binding of the complex to DNA prevents progression through helicase/primase catalytic cycles to replicate viral DNA BILS179 - inhibits DNA helicase complex - freezes it on DNA, cannot move along inhibits growth of acyclovir resistant strains