Herpes Flashcards
Herpes Simplex Virus basics
HSV1, HSV2
entry: epithelial, oral/genital
Primary: 1 - asymptomatic/sore throat
2- genital lesions, severe infection
latent: neurons
reactivation: genital lesions, cold sores
Varicella Zoster Virus
entry: epithelial
primary: chicken pox
latent: neurons
reactivation: shingles/zoster
painful rash and post herpatic neuralgia
live attenuated vaccine for chicken pox, booster for shingles
CMV basics
primary - usually asymptomatic, during pregnancy - birth defects
latent site: PBMC of myeloid lineage
reactivation - macrophage, bring virus around body, immune system usually controls but big problem if immuno suppressed
HHV6, 7
primary: febrile illness for infants - roseola
latent: t cells, brain
reactivation?
EBV basics
entry: epithelial cells
primary: mono, self limiting
latent: b cells
reactivation: if immunosuppressed, clonal B cell expansion, burkitt’s lymphoma or other cancers if immunosuppressed, correlates with geo regions
Kaposi’s Sarcoma Associated Herpesvirus
entry - mucosal epithelia, sex, nonsex, saliva
primary - asymptomatic
latent?
reactivation - kaposi’s sarcoma - hard plaques when immunosuppressed, can kill!
criteria for herpesvirus family
linear dsDNA
capsid
engelope
tegument
glycoproteins
tegument
filled with proteins inside the envelope, outside the capsid
deliver stuff into target cell and capsid goes to nucleus
herpes virus lifecycle
binding and entry
tegument proteins
IE (immediate early)
E (early) - DNA synthesis
L - late
envelopment and egress, DNA processing, capsid assembly
virions
immediate early
first, synthesis of IE mRNAs and polypeptides
global regulators of viral gene expression, 1 immunomodulator
function of IE proteins REQUIRED for activation of E and L genes
anti-sense phosphorothioate
antisense IE genes - target HCMV IE mRNAs
bind and RNase H cleaves mRNA:DNA hybrid
inhibit productive virus replication
Early
synthesis of early mRNA and polypeptides - in nucleus
mostly involved in nt metabolism and viral DNA replication
DNA synthesis initates from viral genome, requires viral and host factors
viral replication machine assembles on genome to replicate DNA
thymidine kinase
phoshorylates thymidine (and analogues - acyclovir)
cellular enzymes generate the active triP
acyclovir has greater affinity for viral tk than cellular tk, so active metabolite is only in infected cells
acyclovir
direct incorporation into replicating DNA results in chains that are no longer substrates for further elongation
competitive inhibition of viral DNA pol
viral tk P acyclovir, cellular kinases activate
acyclovir only has affinity for viral tk
Gangcyclovir
UL97 - protein kinase with cell and viral substrates
BCMV infected cells - not a nt kinase! but P gangcyclovir
important for viral growth
DNA chain terminator BUT has a lot of toxic side effects because very little specificity - can be incormporated into mnormal cell DNA that is replication
Herpesvirus DNA replication
concatemer - rolling circle replication
single, extremely long DNA molecule with tandemly reiterated viral genomes
processing into unit length genomes late in the cycle
linked to assembly of mature viral particles - stuff capsids w DNA
helicase-primase inhibitors
bind to unwind DNA -
composed of 3 proteins
enhance binding to prevent unwinding!
in cases of acyclovir resistance (HIV patients)
Late
synthesis of late mRNA and polypeptides
structural capsid and tegument proteins
scaffold
proteins self assemble into scaffold with protease domain and a small polyprotein
scaffold self digests itself and stuff DNA into capsid with rolling circle replication
Foscarnet
targets DNA polymerase in early stage
herpesvirus host response
generation of neutralizing antibodies against surface glycoproteins (protect against another primary infection)
cellular immunity neutralizes reactivation
immunocomp - can be severe!
herpes virus evasion of immune system
clog proteasome
block TAP
rip MHC I out of ER and degrade
make MHCI decoys proteins
endocytosis of MHC I
also soe MHC II
herpes and abs
grab ab so ag bing sites pointed away from grycoprotein target
HSV latency
trigeminal ganglion, neuronal cell bodies
viral DNA is nuclear, circular, 20 copies/genome
chromatin silences expression!!
only viral products detected - miRs from LAT
respond to local stress/nutrients
LAT
latency associated transcript
virus encodes a repressor of productve cycle genes
repressor encoded byLAT and expressed during latency
suppress apoptosis
EBV latency
latent in B cells
B cells will divide (neurons don’t!)
critical to maintain genome so daughter cells get it
makes proteins during latency
1 copy of nuclear plasmid
LMP-1
transmembrane protein - mimic for B cell CD4-
immortalizes B cell
to immortalize b cells and regulate their proliferation - const activates pways for normal b cell prolif
Notch
deregulate notch through ebna-2 to immortalize b cells and regulate their proliferatin
Zta (Zebra)
signal to mediate EBV reactivation - latent to productive cycle gene expression
viral site specific DNA binding protein/TF
acivates expression of productive cycle genes
results in DNA rep, virus production, death of host cell
