Herpesvirus Flashcards

1
Q

How many human herpesviruses are there?

A

8

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2
Q

What is the structure of herpesvirus?

A
dsDNA 100-250kb genome 
proteinaceous core 
icosahedral capsid 
tegument
enevelope w glycoproteins
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3
Q

what are he 2 life cycles of herpes virus?

A

lytic - produce virions

latent - persist in host

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4
Q

what are the 3 subfamilies of herpesvirus?

A

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

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5
Q

What are characteristics of the alphaherpesvirinae?

A

Variable host range
spread rapidly
latency - SENSORY GANGLIA

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6
Q

What are characteristics of betaherpesvirinae?

A

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

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7
Q

What are characteristics of gammaherpesvirinae?

A

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

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8
Q

How is the HSV genome organised?

A

encodes 80 gene products

2 covalently linked segments - flanked by inverted repeats

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9
Q

What happens during HSV lytic cycle?

A

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

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10
Q

What happens to HSV during latent cycle?

A

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

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11
Q

HSV lytic REPLICATION cycle?

A
attachment/penetration
transcription - IE, DE, late gene expression
Genome replication 
Virus assembly 
Virus envelopment & release
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12
Q

What does virus entry of HSV require?

A

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

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13
Q

How does HSV penetrate the host cell?

A

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

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14
Q

How are HSV lytic genes expressed?

A

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

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15
Q

How is expression of IE initiated?

A

recruitment of cellular factors to IE promoters

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

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16
Q

What are the roles of the IE proteins?

A

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

17
Q

How are PML bodies disrupted to help virus replication?

A

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

18
Q

What are the 7 viral genes essential for genome replication?

A

UL9
ICP8
UL5/8/52
UL30/42

19
Q

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

A

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

20
Q

What is the rolling circle mechanism?

A

circular replication structure is nicked - rolling circle intermediate

forms concatemeric strands of viral progeny DNA

21
Q

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

A
terminase proteins (UL15, UL28, UL33)
they cut concatemeric DNA at specific sites
22
Q

How do the virus capsids exit from nucleus?

A

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

primary envelope fuse w outer nuclear membrane

23
Q

What is involved in HSV virion maturation?

A

capsids associate w tegument proteins

final envelopment - bud into golgi-derived exocytotic vesicles

24
Q

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

A

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

25
Q

Why does HSV go latent in neurons?

A

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

26
Q

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

A

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

27
Q

What is the role of LAT?

A

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

28
Q

How does HSV reactivate from latency?

A

latent episome must reorganise chromatin & ensure levels of IE expression are sufficient to overcome miRNAs

stimuli - HCF-1 & VP16 accumulation

29
Q

What is HSV1?

A

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

30
Q

What is HSV2?

A

genital herpes due to HSV-1 infection

31
Q

What happens to HSV-2 in neonates?

A

Outbreak of HSV2 when pregnant

newborn - weakened immune system = dramatic infection & severe neurological disease

32
Q

What is VSV?

A

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

33
Q

What is EBV?

A

linked to Burkitt’s lymphoma & Hodgkin’s disease

more aggressive in the immunosuppressed

34
Q

How are herpesvirus infections controlled?

A

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

35
Q

How does Acyclovir and other nucleoside analogues act?

A

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

36
Q

How do the new drugs Helicase-primase inhibitors act?

A

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