Herpesvirus Flashcards
How many human herpesviruses are there?
8
What is the structure of herpesvirus?
dsDNA 100-250kb genome proteinaceous core icosahedral capsid tegument enevelope w glycoproteins
what are he 2 life cycles of herpes virus?
lytic - produce virions
latent - persist in host
what are the 3 subfamilies of herpesvirus?
Alphaherpesvirinae - HSV1/2
Beta”” HHV6/7, CMV
Gamma”” KSHV, EBV
What are characteristics of the alphaherpesvirinae?
Variable host range
spread rapidly
latency - SENSORY GANGLIA
What are characteristics of betaherpesvirinae?
Restricted host range
slow cell-cell spread
latency - LYMPHORETICULAR CELLS
What are characteristics of gammaherpesvirinae?
Very restricted host range
Replicate - lymphoblastoid cells
latency - T/B CELLS
How is the HSV genome organised?
encodes 80 gene products
2 covalently linked segments - flanked by inverted repeats
What happens during HSV lytic cycle?
replicates in epithelial cells - in nucleus
infectious particle production & cell destruction
lytic burst = coldsore
What happens to HSV during latent cycle?
Reversible non productive infection of a neuron
can be lifelong state
must evade immune response
HSV lytic REPLICATION cycle?
attachment/penetration transcription - IE, DE, late gene expression Genome replication Virus assembly Virus envelopment & release
What does virus entry of HSV require?
interaction between virus glycoproteins & cellular receptors
gB, gC bind
gD stabilises by binding to entry mediators
How does HSV penetrate the host cell?
pH-independent fusion of viral envelope with plasma membrane
transport to NPC by microtubules
How are HSV lytic genes expressed?
temporal cascae
IE - switch on expression of viral genes
E - enzymes for DNA replication
L - structural genes
How is expression of IE initiated?
recruitment of cellular factors to IE promoters
tegument protein VP16/ alphaTIF enhances expression - interacts with transcription factors
What are the roles of the IE proteins?
ICP0 - promiscuous transactivator, disrupts cellular ND10,
ICP27 - transactivates late genes, acts at posttranscriptional level
ICP4
ICP47
How are PML bodies disrupted to help virus replication?
contain several cellular proteins
utilise PML bodies to enhance virus replication
also disrupt interferon-induced innate immune response
What are the 7 viral genes essential for genome replication?
UL9
ICP8
UL5/8/52
UL30/42
What are the early steps of HSV-1 genome replication?
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
What is the rolling circle mechanism?
circular replication structure is nicked - rolling circle intermediate
forms concatemeric strands of viral progeny DNA
What acts as the ATP-dependent pump that drives DNA into the procapsid?
terminase proteins (UL15, UL28, UL33) they cut concatemeric DNA at specific sites
How do the virus capsids exit from nucleus?
budding at inner nuclear membrane - enveloped primary virions in the perinuclear cleft
primary envelope fuse w outer nuclear membrane
What is involved in HSV virion maturation?
capsids associate w tegument proteins
final envelopment - bud into golgi-derived exocytotic vesicles
How do herpesviruses persistently infect the host via lifelong latent infection?
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
Why does HSV go latent in neurons?
tegument layer containing VP16 and HCF-1 is removed and remains in neuron cytoplasm = NO ACTIVATION of IE lytic gene expression
Why can the adaptive immune system not clear the latently infected neurones?
CNS has limited responses to inflammatory cytokines e.g. IFNs
neurones cannot be replaced - not easily cleared by immune cells
What is the role of LAT?
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
How does HSV reactivate from latency?
latent episome must reorganise chromatin & ensure levels of IE expression are sufficient to overcome miRNAs
stimuli - HCF-1 & VP16 accumulation
What is HSV1?
common cold sore virus
herpes encephalitis - edema, hemorrhages
3.7Bn people have it
What is HSV2?
genital herpes due to HSV-1 infection
What happens to HSV-2 in neonates?
Outbreak of HSV2 when pregnant
newborn - weakened immune system = dramatic infection & severe neurological disease
What is VSV?
Chicken pox
shingles
much more aggressive in elderly
severe pain, damage to nerve endings in skin
What is EBV?
linked to Burkitt’s lymphoma & Hodgkin’s disease
more aggressive in the immunosuppressed
How are herpesvirus infections controlled?
Vaccines
Antivirals - Acyclovir
New drugs - peptide blockers
Novel - block cellular interactions
How does Acyclovir and other nucleoside analogues act?
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
How do the new drugs Helicase-primase inhibitors act?
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
