Herpes Simplex Virus - created from Mind Map

Seite 1

2 Types

Maintains high levels of infection through reactivation and shedding

Endemic in all populations

Neurotropic

Common Sites

Lytic Infection

Latent infection

Treatment

Models

HSV genome

HSV 1

HSV2

Prevalence of antibodies against it increases with age

Mostly oral

Establishes latency in trigeminal ganglion

Reactivation seeds to oral or nasal mucosa

Typically transmitted during childhood

Preferentially establishes latency in neurons with A5 marker

Encephalitis

Mild gingivostomatitis (ulceration and pain when severe)

Shedding in saliva provides transmission route

Maintenance of latency requires NGF interaction with receptor TrkA

Transfer of LAT exon 1 deletes regions responsible for productive infection of A5 + and KH10 +

Express Gal beta1-4GlcNAc-R epitote

Immnoreactive to calcitonin gene-related peptide

Function mapping productive infection between LAT TATA box and Pvul site 44bp

Believed to help by repressing lytic genes or inhibiting apoptosis

Reaches lumbar cord more effectively

Almost identical to HSV2 except for apparent 20bp deletion of region required for productive A5 + infection

Related to ability to establish latency in sympathetic fibers?

Less prevalent type

Mostly genital

Establishes latency in sacral dorsal root ganglia

Preferentially establishes latency in neurons identified with KH10

2 regulatory sequences in LAT for productive infection

Recurrent meningitis

Sexually transmitted but often asymptomatic

Recurs more frequently

Sheds more frequently

More painful

Can remit spontaneously

A5+ permissive for productive infection

Express Gal alpha1-3Gal beta1-4NAc-R epitote

Colabel with lectin BSL-IB4

Population of small-diameter glial cell-line-derived neurotrophic factor-response neurons

Determined in part by LAT

Reaches sacral cord more effectively

dLAT (deletion in promoter) much less effective in A5+

NotI-NotI promotes productive infection in A5 +

LAP2 inhibits productive infection in KH10+

LAT sequence containing 5' exon and LAT intron has essential elements for type-specific reactivation

Transferable

Not transferable as independent functional element

Contributes to virulence

Transcribed from repeat region in antisense direction from ICP0 and ICP345

Spliced into one stable intron (two in HSV1)

Establishes latency in primary sensory neurons

Enters sensory nerve terminals and travels backwards

Travels back to periphery to facilitate epithelial cell infection

Have single bifurcated axon

Reach neurons in a manner proportional to representation in unaffected ganglia

Both types equally permissive for accumulation of HSV-1 and HSV-2 LAT

Both sensory trigeminal ganglion and sympathetic superior ganglion neurons expressed adrenergic receptors and glucocorticoid receptors

Periphery

Spinal cord

Epinephrine treatment increases levels of HSV-1 replication in SCG but not TG

Corticosterone decreases levels of HSV-2 in SCG but not TG

Autonomic neurons more responsive than sensory neurons

Different responses to stress in different HSV types

Neuronal populations express different patterns of receptors

Epinephrine involved in cAMP levels

Autonomic role in pathogenesis

Shows immune suppression may not be only factor

Increased cAMP levels shown to reactivate HSV-1 in SCG

Serum- and glucocorticoid-regulated protein kinases implicated in HSV_1 replication stimulation

Retrograde microtubule-associated transport

Skin

Eye

CNS

Congenital/neonatal

Caused in other dorsal root ganglia by infected secretions

Bad with atopic dermatitis

Major cause of corneal blindness

Recurrent acute bilateral keratoconjuctivitis causing dendritic ulcers

Rare form of encephalitis

Alzheimer's?

Acquired in birth canal or uterus

High mortality

Characterized by classes of gene products

Protein synthesis in cytoplasm, but nucleocapsids assembled in nucleus

Highly cytolytic

Virus enters cytoplasm

Immediate Early

Early

Late

Leaky late

Require presence of VP16

Regulation of viral gene expression

Role in immune invasion

Defined by TAATGARAT VP-16 response elements within promoters

Inhibit host RNA translation

Create an environment for the lytic cycle

Virion transactivator protein

One of the most powerful transcriptional activation domains yet described

Late structural component of tegument layer

Binds to host cell factor 1 w/ nuclear localization sequence

Protein network between envelope and capsid

Transported to nucleus

Forms trimeric complex on consensus VREs in IE promoters

with

Stimulates IE transcription cascade

Impaired by restrictions in member availability?

During reactivation

Molecular trigger following hyperthermic stress?

October binding protein - 1

Homeodomain protein

Downregulated

HCF-1 localized in cytoplasm of sensory neurons

Interacts with

Histone acetyltransferases (CBP/p300)

Chromatin remodeling factors (BGRT-1 and BRM)

Histone methyltransferases (HMT's)

Lysine-specific demethylase-1 (LSD-1)

If so, Oct-1 and HCF-1 also probably important

HCF-1 relocalizes from Golgi to nucleus and associates with promoters

Recruits LSD to reverse repressive methylation at IE promoters

IE1 (ICP0)

IE2 (ICP27)

IE3 (ICP4)

IE4 (ICP22)

Likely has crucial role in reactivation

Roles

Harbors E3 ubiquitin ligase RING finger domain

Disrupts CoREST/REST repressor complex

Most likely candidate for initiation of lytic expression and exit from latency

ND10 bodies (similar distribution)

Nuclear accumulations of proteins regulated by interferons

Role in replication of DNA viruses

Domain change to favor lytic transcription?

Transcription factors associated with domains

Associations with cell proteins involved in transcription

Cell cycle regulation

DNA repair

Interferon response

Degrades constituents of ND10 bodies

Dissociation of HDACs 1/2

Interacts with HDACs 4, 5, 7

Antagonizing cellular repression such as histone-mediated silencing

Role during reactivation

Recruitment of LSD1 to IE promoters by HCF1 crucial for both initiation and reactivation

Recruited by repressor element-1 silencing transcription

Component of cellular repressor complex

Can function as corepressor

CoREST may also:

Demethylate histone H3K4

Repress neuronal gene expression in cells that aren't nerves

Function as a coactivator by demethylating repressive H3K9 marks at IE promoters

Interact with ICP0 to disrupt corepressor complex

Interferes with cell death during lytic cycle

IE5 (ICP47)

Major MHC class 1 evasion gene

Disrupts RNA splicing machinery

Promote nuclear export of viral mRNA via ICP27 and CD8 + T cell evasion

Dependent on synthesis of IE products

Seven required for viral DNA replication

Some involved in changing cell environment to support rapid DNA synthesis

Enzymes required for DNA replication

Thymidine kinase

Ribonucleotide reductase

Dependent on prior synthesis of viral DNA

Mostly structural components

Recognize viral genomes

Exits via budding through nuclear membrane

Mature envelope and glycoproteins acquired in membrane-bound organelles

Cleaved into monomers as they are packaged

Capsid transported via microtubule to nucleus

Docks to nuclear pore

DNA released into nucleus

Present in neurons but not satellite cells

Still transcription from viral genome

Establishment of latency

Reactivation

Latency associated transcripts

Overlap IE1 but on opposite strand

Minor LAT

Major LAT

Transcribed from a locus within the repeat regions flanking the ULR

miRNAs by LAT locus

Probably not translated into functional protein in vivo

sRNAs

Not transcribed in all infected

Polyadenylated

Localized to discrete intranuclear foci

8.3 kb

Stable introns spliced from primary LAT transcript

Contains two open reading frames

1.5 & 2 kb

Likely contributes to rapid turnover

Implicated in

Raise coding capacity

Nonimmunogenic

16 in HSV1

18 in HSV 2

Latent/lytic control

Immune evasion

Cell survival

Within 8.3 LAT

Just upstream of start site

1-8 expressed during latency

miRNA-H2

miRNA-H3

miRNA-H4

miRNA-H5

miRNA-H7

miRNA-H8

Shown to reduce ICP0 abundance

Shown to reduce ICP4 abundance

miRNA-H1

miRNA-H6

Overlap

Abundant during productive infection

miRNA-H2 shown to inhibit ICP0

miRNA-H3 & -H4 down regulate neurovirulence factor expression

miRNA?

Capable of inhibiting productive infection in culture

sRNA2 weaker

sRNA1 appears to mediate anti-apoptosis activity

Down regulated ICP4 accumulation

Did not affect RNA levels

Dynamic expression?

Viruses w/o VP16 can't initiate lytic cycle, but can establish latent infection in vivo

Default pathway?

Diverges immediately upon infection

Replication required to be effective

Not mutually exclusive with lytic infection?

Large load may be indicative of abortive lytic infection

Potential for noncytolytic CD8 + T cell inhibition in HSV-1 replication

Large load may predispose to reactivation

Block in expression via IFN gamma secretion and Granzyme B

Also likely to play role in reactivation control

However, specific for immunodominant glycoprotein B epitote - not IE

Copies per cell variable

# of input genomes?

Limited expression prior to latency?

Efficiency at periphery?

Failure of ICP0 expression and genome circularization first step to latency?

Triggers

Molecular Basis

In culture only, leads to rapid spread

Immunosuppression

Febrile illness

UV exposure

Stress

Nerve damage/removal

Removal of neurotropic factor?

Activation of cAMP and protein-kinase C-dependent second messenger pathways?

Heat stressing and corticosteroid treatment

Activation of second messenger systems?

Different from initial infection

CD8+ T cells

Nucleosomally associated rather than extruded

Transcriptionally repressed

No VP16

Recognize glycoprotein B

Just respond to lytic transcript expression?

Suppress reactivation?

Acyclovir = mainstay

Alternates

Resistance rare except in immunocompromised

Future

Converted to active form by viral TK and cellular kinases

Topically, orally, intravenously

Every four hours

Shortens episodes

Reduces recurrences

Incorporated into viral genome, acting as a chain terminator and inhibiting replication

Acyclovir triphosphate

Valacyclovir

Famicyclovir

Penciclovir

Cidoform

Foscarnet

Attacks viral DNA polymerase

Pyrophosphate analogue

Competitively binds DNA polymerase

Prevents chain elongation

Interfere with latency establishment?

Eradicate latent genomes

Vaccination?

Target LATs?

Target IE genes and ICP0

Animal models

In vitro

Humans only natural host

Mouse

Rabbit eye

Guinea pigs

Infection of eye, flank or footpad

Latent infection established but rarely reactivated

Replication at local epithelial site

Transport via axon to sensory neurons

Hypothermia

CD8+ T cell depletion

Skin abrasion

Cornea infected

No spontaneous reactivation

Latency established in trigeminal ganglion

Virus shed in tears

Reproduces clinical course of human infection but not amenable to detailed molecular study

Relies on antiviral drugs or replication defective mutants

Reactivation triggers

Viral genome circularized

LAT expression and virus reactivation only in neuronal systems

Latency established using unnatural block

Preferred neuron types reverse

NGF withdrawal

Histone deacetylase inhibition

ICP0 expression

In sensory ganglia derived from mice

Forskolin

Inducible cyclic AMP early repressor

Capsaicin

Capsase-3 activator C2-ceramide

Protein kinase C activation by phorbol myristate acetate

Transient hypothermia

Sensed by TrkA receptor

Epidermal growth factor (EGF) and GDNF can signal through same pathway, but do not really maintain latency

Responsive A5 + neurons largely calcitonin gene-related peptide-positive

Activates phosphalidylinositol 3-kinase (PI3-K) catalytic subunit

Recruitment of 3-phosphoinositide-dependent protein kinase-1 (PDK1) to plasma membrane

Phosphorylation of serine/threonine kinase Akt

Glial cell line-derived neurotrophic factor-responsive K10 + C fiber neurons colabel with isolectin-B4

Trichostatin A

Heat shock

Treatment with dexamethasone

Linear, double-stranded, 152 kb

Two long and two short regions

Circularizes following nuclear entry

Theta replication at 3 origins, then rolling circle

Maintained as a circle during latency

Cocantemers cléaved into monomeric units

Assembled into nucleosomes

Associated with reversible and nonreversible and nonreversible repressive chromatin modifications

Structure to mediate epigenetic control regulated by PTMs of histones

Euchromatin-like modifications

Heterochromatin-like modifications

Enrichment of acetylated H3K9 and H3K14 at LAT promote and enhancer during latency

Lytic genes enriched w/ methylated H3K27 during latency

Acetylation of H3K9 and H3K14

Enriched in lytic infection

Dimethylation of H3K9

Underrepresented