Herpesvirusesoverview

1
Herpesviruses-overview

• general properties
• clinical
• structure
• HSV-1 regulatory proteins
• HSV-1 regulatory protein ICP27

2
Herpesviruses general herpes simplex virus-1
2005

• J Barklie Clements
• b.clements_at_vir.gla.ac.uk
• tel [phone]

3
General
4
Herpesviruses-general

• Baltimore class 1 (dsDNA)
• less reliant on cell enzymes
• transcription is regulated temporally in a
  cascade

5
Herpesviruses-general

• infect most vertebratesfish, birds,
  marsupials,mammals
• cause lytic lifelonglatent infections
• can recur

6
Human herpesviruses
7
Clinical
8
Herpes simplex-1

• oral genitallesions

9
Herpes simplex-2 -1

• genital lesions
• neurotropic

10
Genital herpes increasing
11
Varicella-zoster

• chickenpox
• recurs asshingles

12
Varicella-zoster

• blisters contain 108 virus
• no cell culture system existsfor replication

13
Epstein-Barr

• Burkitts lymphoma
• 6 days aftertreatment

14
Human cytomegalovirus

• congenitalinfections
• deformed skull(microcephaly)

15
Human herpesvirus-8

• Kaposis sarcoma
• blood vessels
• AIDS-associated

16
Structure
17
Herpesviruses-structure

• large enveloped virions
• all are similar
• icosahedron
• 12 pentamers (ateach apex) 150 hexamers

18
HSV-structure

• tegumentjelly-like,withVP16 Vmw65
  regulatoryproteins

19
Herpesviruses-genomes

• ds linear DNA
• 100-250kbp
• unique and repetitive regions
• 80-100 proteinsencoded

20
Herpesviruses-genomes
21
HSV-1Life cycles
22
HSV lytic replication
23
HSV proteins

• viral cell gene regulatory (immediate early
  late)
• viral DNA replication accessory (early)
• virion structural (late)

24
HSV-latency

• genome present
• no replication cycle
• no virus particles

25
HSV-reactivation

• stress, UV, immune suppression
• needs viral immediate early (IE) ICP0 protein
• occurs only in a few neurones

26
HSV-latency
27
HSV/VZV can infect the CNS
28
HSV-1 regulatoryproteins
29
Tegument regulatory proteins

• Vhs degrades cell mRNAs, causes host shut off
• VP16 activates viral IE gene expression

30
Vhs acts in cytoplasm VP16in nucleus
31
VP16 action

• binds cell OCT-1in nucleus
• OCT-1 bindsTAATGARATupstream of the 5 IE gene
  promoters only
• VP16-OCT-1 complex recruits transcription
  factors, activating IE genes

32
IE regulatory proteins

• ICPO latency reactivation
• ICP22 alters RNA pol II phosphorylation
• ICP47 inhibits MHC class I system
• ICP4 viral transcription factor
• ICP27 post-transcriptional,multifunctional

33
HSV-1 regulatoryproteinICP27
34
ICP27

• essential counterpart in every herpesvirus
• inhibits host pre-mRNA splicing (host shutoff)
• promotes viral mRNA nuclear export
• stimulates viral mRNA translation

35
Post-transcriptional events
36
ICP27 is multifunctional

• acts by interaction with different cellular
  proteins, by binding viral RNA
• co-ordinates the different stages ofviral gene
  expression

37
ICP27-cell protein partners

• casein kinase 2 (phosphorylatesproteins,
  activates represses)
• spliceosome associated proteinSAP145
• RNA export factor REF
• poly(A) binding protein PAB

38
ICP27 domains

• nuclear export(NES)
• nuclear localisation(NLS)
• RNA binding(RGG box)
• zinc finger forprotein-protein interaction

39
Cell RNA export

• REF TAP
• are depositedon cell mRNAs during splicing
• TAP interactswith nuclearpores

40
ICP27-viral mRNA export

• HSV mRNAslack introns
• ICP27 bindsviral mRNAsdirectly recruitsREF
  via protein
• protein interaction
• to facilitate their export

41
ICP27 binds cell poly(A)binding protein (PABP)

• PABP binds the 3 poly(A) tail proteins on the
  5 mRNA cap
• this forms closed loop mRNAnecessary for
  interaction withribosomes translation
  initiation

42

43
Herpesviruses-overview

• general properties
• clinical
• structure
• HSV-1 regulatory proteins
• HSV-1 regulatory protein ICP27