Herpes Simplex Virus

2 Types
1. HSV 1
  1. Prevalence of antibodies against it increases with age
  2. Mostly oral
    1. Mild gingivostomatitis (ulceration and pain when severe)
    2. Shedding in saliva provides transmission route
  3. Establishes latency in trigeminal ganglion
  4. Reactivation seeds to oral or nasal mucosa
  5. Typically transmitted during childhood
  6. Preferentially establishes latency in neurons with A5 marker
    1. Maintenance of latency requires NGF interaction with receptor TrkA
    2. Transfer of LAT exon 1 deletes regions responsible for productive infection of A5 + and KH10 +
      1. Function mapping productive infection between LAT TATA box and Pvul site 44bp
        Almost identical to HSV2 except for apparent 20bp deletion of region required for productive A5 + infection
      2. Believed to help by repressing lytic genes or inhibiting apoptosis
      3. Reaches lumbar cord more effectively
        Related to ability to establish latency in sympathetic fibers?
    3. Express Gal beta1-4GlcNAc-R epitote
    4. Immnoreactive to calcitonin gene-related peptide
  7. Encephalitis
2. HSV2
  1. Less prevalent type
  2. Mostly genital
    1. Sexually transmitted but often asymptomatic
    2. Recurs more frequently
    3. Sheds more frequently
    4. More painful
    5. Can remit spontaneously
  3. Establishes latency in sacral dorsal root ganglia
  4. Preferentially establishes latency in neurons identified with KH10
    1. A5+ permissive for productive infection
      1. Determined in part by LAT
      2. Reaches sacral cord more effectively
    2. Express Gal alpha1-3Gal beta1-4NAc-R epitote
    3. Colabel with lectin BSL-IB4
    4. Population of small-diameter glial cell-line-derived neurotrophic factor-response neurons
  5. 2 regulatory sequences in LAT for productive infection
    1. dLAT (deletion in promoter) much less effective in A5+
    2. NotI-NotI promotes productive infection in A5 +
      1. Transferable
    3. LAP2 inhibits productive infection in KH10+
      1. Not transferable as independent functional element
    4. LAT sequence containing 5' exon and LAT intron has essential elements for type-specific reactivation
      1. Contributes to virulence
      2. Transcribed from repeat region in antisense direction from ICP0 and ICP345
      3. Spliced into one stable intron (two in HSV1)
  6. Recurrent meningitis
Maintains high levels of infection through reactivation and shedding
Endemic in all populations
Neurotropic
1. Establishes latency in primary sensory neurons
  1. Travels back to periphery to facilitate epithelial cell infection
  2. Have single bifurcated axon
    1. Periphery
    2. Spinal cord
  3. Reach neurons in a manner proportional to representation in unaffected ganglia
  4. Both types equally permissive for accumulation of HSV-1 and HSV-2 LAT
  5. Both sensory trigeminal ganglion and sympathetic superior ganglion neurons expressed adrenergic receptors and glucocorticoid receptors
    1. Epinephrine treatment increases levels of HSV-1 replication in SCG but not TG
    2. Corticosterone decreases levels of HSV-2 in SCG but not TG
    3. Autonomic neurons more responsive than sensory neurons
      1. Autonomic role in pathogenesis
    4. Different responses to stress in different HSV types
      1. Shows immune suppression may not be only factor
    5. Neuronal populations express different patterns of receptors
    6. Epinephrine involved in cAMP levels
      1. Increased cAMP levels shown to reactivate HSV-1 in SCG
      2. Serum- and glucocorticoid-regulated protein kinases implicated in HSV_1 replication stimulation
2. Enters sensory nerve terminals and travels backwards
  1. Retrograde microtubule-associated transport
Common Sites
1. Skin
  1. Caused in other dorsal root ganglia by infected secretions
  2. Bad with atopic dermatitis
2. Eye
  1. Major cause of corneal blindness
  2. Recurrent acute bilateral keratoconjuctivitis causing dendritic ulcers
3. CNS
  1. Rare form of encephalitis
  2. Alzheimer's?
4. Congenital/neonatal
  1. Acquired in birth canal or uterus
  2. High mortality
Lytic Infection
1. Characterized by classes of gene products
  1. Immediate Early
    1. Require presence of VP16
      1. Virion transactivator protein
      2. One of the most powerful transcriptional activation domains yet described
      3. Late structural component of tegument layer
        Protein network between envelope and capsid
      4. Binds to host cell factor 1 w/ nuclear localization sequence
        Transported to nucleus
        Forms trimeric complex on consensus VREs in IE promoters
        with
        October binding protein - 1
        Downregulated
        Homeodomain protein
        HCF-1 localized in cytoplasm of sensory neurons
        Stimulates IE transcription cascade
        Impaired by restrictions in member availability?
        During reactivation
        Interacts with
        Histone acetyltransferases (CBP/p300)
        Chromatin remodeling factors (BGRT-1 and BRM)
        Histone methyltransferases (HMT's)
        Lysine-specific demethylase-1 (LSD-1)
        Molecular trigger following hyperthermic stress?
        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
    2. Regulation of viral gene expression
      1. IE1 (ICP0)
        Likely has crucial role in reactivation
        ND10 bodies (similar distribution)
        Nuclear accumulations of proteins regulated by interferons
        Role in replication of DNA viruses
        Transcription factors associated with domains
        Domain change to favor lytic transcription?
        Associates with proteins involved in
        Cell cycle regulation
        Interferon response
        DNA repair
        Transcription
        Harbors E3 ubiquitin ligase RING finger domain
        Degrades constituents of ND10 bodies
        Disrupts CoREST/REST repressor complex
        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
        Component of cellular repressor complex
        Recruited by repressor element-1 silencing transcription
        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
        Most likely candidate for initiation of lytic expression and exit from latency
      2. IE2 (ICP27)
        Interferes with cell death during lytic cycle
      3. IE3 (ICP4)
      4. IE4 (ICP22)
    3. Role in immune invasion
      1. IE5 (ICP47)
        Major MHC class 1 evasion gene
    4. Defined by TAATGARAT VP-16 response elements within promoters
    5. Inhibit host RNA translation
      1. Disrupts RNA splicing machinery
      2. Promote nuclear export of viral mRNA via ICP27 and CD8 + T cell evasion
    6. Create an environment for the lytic cycle
  2. Early
    1. Dependent on synthesis of IE products
    2. Seven required for viral DNA replication
    3. Some involved in changing cell environment to support rapid DNA synthesis
      1. Thymidine kinase
      2. Ribonucleotide reductase
    4. Enzymes required for DNA replication
  3. Late
    1. Dependent on prior synthesis of viral DNA
    2. Mostly structural components
  4. Leaky late
2. Protein synthesis in cytoplasm, but nucleocapsids assembled in nucleus
  1. Recognize viral genomes
    1. Cleaved into monomers as they are packaged
  2. Exits via budding through nuclear membrane
  3. Mature envelope and glycoproteins acquired in membrane-bound organelles
3. Highly cytolytic
4. Virus enters cytoplasm
  1. Capsid transported via microtubule to nucleus
    1. Docks to nuclear pore
      1. DNA released into nucleus
Latent infection
1. Present in neurons but not satellite cells
2. Still transcription from viral genome
  1. Latency associated transcripts
    1. Overlap IE1 but on opposite strand
    2. Minor LAT
      1. Polyadenylated
      2. Localized to discrete intranuclear foci
      3. 8.3 kb
    3. Major LAT
      1. Stable introns spliced from primary LAT transcript
      2. Contains two open reading frames
      3. 1.5 & 2 kb
    4. Transcribed from a locus within the repeat regions flanking the ULR
    5. miRNAs by LAT locus
      1. Likely contributes to rapid turnover
      2. Implicated in
        Latent/lytic control
        Immune evasion
        Cell survival
      3. Raise coding capacity
      4. Nonimmunogenic
      5. 16 in HSV1
        Within 8.3 LAT
        miRNA-H2
        Shown to reduce ICP0 abundance
        miRNA-H3
        Shown to reduce ICP4 abundance
        miRNA-H4
        miRNA-H5
        miRNA-H7
        miRNA-H8
        Just upstream of start site
        miRNA-H1
        miRNA-H6
        Overlap
        Abundant during productive infection
        1-8 expressed during latency
      6. 18 in HSV 2
        miRNA-H2 shown to inhibit ICP0
        miRNA-H3 & -H4 down regulate neurovirulence factor expression
    6. Probably not translated into functional protein in vivo
      1. miRNA?
    7. sRNAs
      1. Capable of inhibiting productive infection in culture
      2. sRNA2 weaker
        Down regulated ICP4 accumulation
        Did not affect RNA levels
      3. sRNA1 appears to mediate anti-apoptosis activity
    8. Not transcribed in all infected
      1. Dynamic expression?
3. Establishment of latency
  1. Viruses w/o VP16 can't initiate lytic cycle, but can establish latent infection in vivo
  2. Default pathway?
  3. Diverges immediately upon infection
    1. Large load may be indicative of abortive lytic infection
      1. Large load may predispose to reactivation
    2. Potential for noncytolytic CD8 + T cell inhibition in HSV-1 replication
      1. Block in expression via IFN gamma secretion and Granzyme B
      2. Also likely to play role in reactivation control
        However, specific for immunodominant glycoprotein B epitote - not IE
  4. Replication required to be effective
    1. Copies per cell variable
      1. # of input genomes?
      2. Limited expression prior to latency?
      3. Efficiency at periphery?
  5. Not mutually exclusive with lytic infection?
    1. Failure of ICP0 expression and genome circularization first step to latency?
4. Reactivation
  1. Triggers
    1. Immunosuppression
    2. Febrile illness
    3. UV exposure
    4. Stress
    5. Nerve damage/removal
    6. Removal of neurotropic factor?
    7. Activation of cAMP and protein-kinase C-dependent second messenger pathways?
    8. Heat stressing and corticosteroid treatment
  2. Molecular Basis
    1. Activation of second messenger systems?
    2. Different from initial infection
      1. Nucleosomally associated rather than extruded
      2. Transcriptionally repressed
      3. No VP16
    3. CD8+ T cells
      1. Recognize glycoprotein B
        Suppress reactivation?
      2. Just respond to lytic transcript expression?
  3. In culture only, leads to rapid spread
Treatment
1. Acyclovir = mainstay
  1. Converted to active form by viral TK and cellular kinases
    1. Acyclovir triphosphate
  2. Topically, orally, intravenously
  3. Every four hours
  4. Shortens episodes
  5. Reduces recurrences
  6. Incorporated into viral genome, acting as a chain terminator and inhibiting replication
2. Alternates
  1. Valacyclovir
  2. Famicyclovir
  3. Penciclovir
  4. Cidoform
    1. Attacks viral DNA polymerase
  5. Foscarnet
    1. Pyrophosphate analogue
    2. Competitively binds DNA polymerase
      1. Prevents chain elongation
3. Resistance rare except in immunocompromised
4. Future
  1. Interfere with latency establishment?
  2. Eradicate latent genomes
    1. Target LATs?
    2. Target IE genes and ICP0
  3. Vaccination?
Models
1. Animal models
  1. Humans only natural host
  2. Mouse
    1. Infection of eye, flank or footpad
      1. Replication at local epithelial site
        Transport via axon to sensory neurons
    2. Latent infection established but rarely reactivated
      1. Hypothermia
      2. CD8+ T cell depletion
      3. Skin abrasion
  3. Rabbit eye
    1. Cornea infected
      1. Latency established in trigeminal ganglion
        Virus shed in tears
    2. No spontaneous reactivation
  4. Guinea pigs
    1. Reproduces clinical course of human infection but not amenable to detailed molecular study
2. In vitro
  1. Relies on antiviral drugs or replication defective mutants
  2. Reactivation triggers
    1. NGF withdrawal
      1. Sensed by TrkA receptor
        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
      2. Epidermal growth factor (EGF) and GDNF can signal through same pathway, but do not really maintain latency
        Glial cell line-derived neurotrophic factor-responsive K10 + C fiber neurons colabel with isolectin-B4
      3. Responsive A5 + neurons largely calcitonin gene-related peptide-positive
    2. Histone deacetylase inhibition
      1. Trichostatin A
    3. ICP0 expression
    4. In sensory ganglia derived from mice
      1. Heat shock
      2. Treatment with dexamethasone
    5. Forskolin
    6. Inducible cyclic AMP early repressor
    7. Capsaicin
    8. Capsase-3 activator C2-ceramide
    9. Protein kinase C activation by phorbol myristate acetate
    10. Transient hypothermia
  3. Viral genome circularized
  4. LAT expression and virus reactivation only in neuronal systems
  5. Latency established using unnatural block
  6. Preferred neuron types reverse
HSV genome
1. Linear, double-stranded, 152 kb
  1. Two long and two short regions
  2. Circularizes following nuclear entry
  3. Theta replication at 3 origins, then rolling circle
    1. Cocantemers cléaved into monomeric units
  4. Maintained as a circle during latency
    1. Assembled into nucleosomes
      1. Structure to mediate epigenetic control regulated by PTMs of histones
        Euchromatin-like modifications
        Acetylation of H3K9 and H3K14
        Enriched in lytic infection
        Heterochromatin-like modifications
        Dimethylation of H3K9
        Underrepresented
        Enrichment of acetylated H3K9 and H3K14 at LAT promote and enhancer during latency
        Lytic genes enriched w/ methylated H3K27 during latency
    2. Associated with reversible and nonreversible and nonreversible repressive chromatin modifications
Sources Used:
1. Lachmann, R. (2003). Herpes simplex virus latency. Expert Reviews in Molecular Medicine, 5(29), 1-14. doi:10.1017/S1462399403006975
2. Margolis, T., Imai, Y., Yang, L., Vallas, V., & Krause, P. (2007). Herpes simplex virus type 2 (HSV-2) establishes latent infection in a different population of ganglionic neurons than HSV-1: Role of latency-associated transcripts. Journal of Virology, 1872-1878. doi:10.1128/JVI.02110-06
3. Ives AM, Bertke AS. 2017. Stress hormones epinephrine and corticosterone selectively modulate herpes simplex virus 1 (HSV-1) and HSV-2 productive infections in adult sympathetic, but not sensory, neurons. J Virol 91:e00582-17.
4. Michael P. Nicoll, João T. Proença, Stacey Efstathiou; The molecular basis of herpes simplex virus latency, FEMS Microbiology Reviews, Volume 36, Issue 3, 1 May 2012, Pages 684–705, https://doi.org/10.1111/j.1574-6976.2011.00320.x
5. Bertke AS, Patel A, Krause PR. 2007. Herpes simplex virus latency-associated transcript sequence downstream of the promoter influences type-specific reactivation and viral neurotropism. J Virol 81:6605–6613. 10.1128/JVI.02701-06.
6. Bertke AS, Ma A, Margolis MS, Margolis TP. 2013. Different mechanisms regulate productive herpes simplex virus 1 (HSV-1) and HSV-2 infections in adult trigeminal neurons. J Virol 87:6512–6516. 10.1128/JVI.00383-13.

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Herpes Simplex Virus

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	Created by Miranda Barnes over 7 years ago