Herpes simplex viruses Flashcards
Feature of genome in herpes virus
linear ds DNA
–> circularize upon cell infection
Three layers in herpes virion (from outer to inner)
i) envelope (with glycoprotein)
ii) tegument
iii) core
what is found in tegument of herpes virus?
viral, clelular proteins
Types of mammalian herpesviruses
alpha, beta, gamma herpesvirus
example of alpha herpesvirus
herpes simplex virus
example of beta herpesvirus
CMV
example of gamma herpesvirus
EBV
Difference between location of latent infection in herpes simplex and CMV
simplex: neurons
CMV: monocytes
Components of genome
i) Long (L)
ii) Short (S)
features of each gene component
i) unique sequence (U) flanked by inverted repeats
ii) L, S can be in any order
steps for HSV entry into cells
i) virus attach to cell surface receptor
ii) viral envelope fuse with plasma membrane
iii) capsid transported to nuclear pore
iv) DNA released into nucleus
what does virus bind to for entry?
gD: specific cell receptor
gH/gL: integrins
what helps with fusion of HSV with plasma membrane?
gB
How does the capside of HSV enter nucleus?
help of microtubules, transported to nuclear pore
What enters nucleus after capsid is transported to nuclear pore?
DNA, tegument proteins
Sequence of gene expression in HSV
i) alpha genes (immediate early)
ii) beta genes (early)
iii) gamma genes (Late)
what does gamma genes expresses?
structural proteins like capsid, envelope, tegument
What does beta gene express?
help in nucleic acid metabolism, DNA synthesis
when is beta genes in HSV expressed?
after alpha genes
what does alpha genes in HSV express?
regulatory proteins needed for gene expression
when does gamma genes express?
after DNA synthesis
What helps induce 1st viral gene expression in HSV?
VP16
How does VP16 induce viral gene expression?
bind to cellular protein (Oct1) that binds to alpha genes promoter
Function of ICP27
i) inhibit transcription, splicing of cellular genes
ii) role in mRNA transport
iii) activate expression of viral beta and gamma genes
What happens after VP16 bind to Oct1?
i) activate expression of alpha genes
-> also need binding to host transcription factor (HCF-1)
which viral proteins are expressed after help for VP16 in HSV?
4 IE proteins (ICP0, 4, 22, 27)
what is VP16?
tegument protein that is delivered to cell upon infection
Targets for ICP0 in HSV?
i) DNA repair proteins
ii) PML proteins
Function of ICP0 in HSV
i) promote lytic infection + needed to activate HSV from latent state
ii) degrade certain proteins like DNA repair ones and PML proteins
What happens when HSV lack ICP0?
i) PML bodies form at incoming viral DNA
–> sequester viral DNA, proteins
–> prevent viral gene expression, DNA replication
How does ICP27 in HSV alter splicing of cellular transcript?
i) inhibit activity of cellular splicing factors
ii) relocalize cellular REF (export proteins) to viral mRNA
How does ICP27 help with mRNA transport?
binds to mRNA lacking introns and recruit REF (export protein) to viral mRNA
–> increased export of viral mRNA and opposite for cellular ones
What cellular processes are inhibited in HSV infection?
i) host DNA synthesis (unable to enter S phase)
ii) glycosylation of host proteins
iii) host protein synthesis
What reduces the protein synthesis of host in HSV infection?
i) ICP27
ii) vhs
How is host protein synthesis reduced in HSV infection?
i) ICP recruit RNA pol II to viral replication site (unable to transcribe cell ones)
ii) ICP inhibit cellular mRNA export to cytoplasm by recruiting REF to viral mRNA
iii) mRNA degraded by vhs
what does VHS stand for?
virion host shut-off
function of vhs
destablize and degrades host and viral mRNA
How does vhs degrade host and viral mRNA
i) vhs bind to host translation factors
–> bring it to polyribosome
ii) 5’ cap removed from mRNA –> then degraded
What happens after vhs takes action?
i) remove pre-existing host mRNA – allow viral mRNA to take over translation pool
ii) destablize viral mRNA
–> transition from one class to another
What controls the activity of vhs?
VP16 that is made late in infection
–> inhibit vhs activity
What happens after VP16 binds to vhs?
packaged into virion
How many origins of replication are found in HSV?
3
Where are origins of replication found in HSV?
1 in L, 2 in S
Viral proteins needed for replication of HSV DNA
i) UL9
ii) DNA pol
iii) ssDNA binding protein
iv) DNA pol processivity factor
v) complex with primase, DNa helicase activity
Function of UL9 in HSV DNA replication
recognizes origin sequence + act as DNA helicase
mechanism behind HSV DNA replication
theta structure
–> tho make linear dsDNA concatamer
What happens before viral DNA into capsid?
scaffold destroyed by VP24
Where does DNA packaging start for HSV?
packaging sequence
describe steps in DNA packaging of HSV
i) capsid recognize complex formed on packaging sequence (a)
ii) DNA into capsid until capsid full and contact with another packaging sequence
iii) DNA cleaved with a sequence
–> asymmetric cleavage to make overhands
Where is virion of HSV first eneloped?
nuclear membrane with viral proteins
How does virions move from golgi to cell surface?
secretory vesicle
Where do u get final envelope for virion of HSV?
golgi
describe steps in viral egress of HSV
i) first enveloped in nuclear membrane
ii) enveloped virion enter ER
iii) lose envelope when exiting ER, gain another one in golgi
–> tegument proteins gained in cytoplasm
iv) Virions move from golgi to cell surface in secretory vesicles
Where does virion lose its first envelope?
exiting ER
Where does latent infection happen in HSV?
sensory neurons that innervate epihtelial cells
transcript(s) expressed in latent HSV infection
latency associated transcript (LAT)
Difference between lytic and latent infection of HSV
i) histone: lytic genes with histone for latent, no histone in lytic infection
ii) viral protein: only expressed in lytic cycle
iii) gene expression:
- LAT in latent
- alpha, beta, gamma genes
Difference in histone modification for lytic and latent infection of HSV
lytic: no histone on promoter
latent: histone on lytic gene promoter (heterochromatin)
Where is LAT expressed?
neuron-specific promoter with histone modifications allow TF access
What protects LAT from heterochromatin modification?
insulator element
function of LAT?
repress lytic gene expression in sensory neurons
how does LAT repress lytic gene expression in HSV?
i) inhibit ICP0 expression by binding to its transcript
ii) miRNA encoded by LAT might also suppress
When is HSV reactivated?
periodically
How is reactivation induced experimentally?
i) express ICP0
ii) treat with histone deacetylase inhibitors
What can promote reactivation of HSV?
i) physical/emotional stress
ii) hormonal change
iii) UV light
Describe steps in reactivation of HSV
i) removed repression of chromatin –> VP16 expressed
ii) VP16 interact with HCF-1 in cytoplasm
–> bring into nucleus
iii) VP16/HCG-1 assemble on viral promoter (Oct 1 helps)
–> activate viral gene expression
iv) viral DNA replication
v) viral particles made and move to cells near initial infection site
HSV with clinical attention
HSV-1, HSV-2
Which HSV infection is more commonly infected?
HSV-1
where does HSV-1 infection occur?
mostly mouth, sometimes genital areas
Where does HSV-2 infection occur?
genitals
complications in HSV infection
i) in newborns (damage eye or destroy parts of brain)
ii) to eyes (more of an issue for immunocompromised)
