Characteristics of HSV
• DNA double stranded virus, linear
• 125-250 Kb long, relatively big
• Enveloped
• Virion size 200 nm, relatively big
• 9 HSVs, Ex. Varicella, EBV, CMV
• Diseases: Chickenbox, Mononucleosis,
  Hepatitis, Encephalitis
• Recurrent eye, mouth and genital lesions

                                             Chickenpox, Varicella
   Herpes Virus and Common Diseases
• Everybody knows chickenpox and likely you experienced the disease
  as a child, can be dangerous when exposed to it in adulthood
• Another common ailment is lip and mouth “cold sores”
• Genital Herpes lesions caused by HSV, sexually transmitted
• HSV-1 cold sores (mild but annoying diseases)
• HSV-2 genital herpes
• Varicella zoster: chickenpox
• However the Herpes family is huge, over 100 members
      HSV-1 Cold sore                HSV-2 Genital Herpes
  HSV Establishes Latent Infections
• Once infection has taken place HSV can remain dormant
  for months, years, lifetime
• Cell types that HSV can infect and remain dormant
   – Neurons, B-cells and T-cells
• Examples:
   – Shingles which can appear years after first chickepox infection
     (caused by varicella zoster, causes both chickenpox and shingles)
   – Genital Herpes outbreaks
Herpes (1-2) Simplex Virus Genome
                      HSV Capsid
• Enclosed in an envelope
• Capsid has icosahedral structure
• Capsid is bilayered
• Constructed from 6 proteins
   – VP5 is the main one
• Envelope contains at least 10 different glycoproteins gB-gM
• Envelope also contains non-glycosylated proteins
HSV Entry Into Host Occurs Via Heparan Sulfate Proteoglycans
•   gB and gC bind to host glycoproteins with heparan sulfate moieties (repeating
    dissacharide: glucoronic and n-acetyl glucosamine)
•   Following gB and gC is gD which binds to nectin1D
•   OR HVEM (herpes virus entry mediator)
•   Fusion occurs between viral envelope and host membrane
•   Nucleocapsid is released into cytosol OR in acidified endosomes
•   Transport to nuclear envelope occurs via T and capsid interaction
•   DNA is released into nucleus
•   Capsid disintegrates

   Genome Expression in Nucleus
• Viral DNA is circularized once inside nucleus
• Viral DNA is localized in regions referred to as ND10
  (nuclear domain 10)
• Viral genes transcribed by cellular RNA Poly II
• Gene expression divided into 4 groups
• Group  occurs within hours of viral infection (these genes
  also referred to as “immediate early genes”)
•  genes (early genes) transcription occurs 4-8 hrs past
   –  genes involved with viral DNA replication
• 1 and 2 (late genes) are the bulk of viral genes
                  Tegument Proteins
• -TIF (a-trans-inducing factor) interacts w/Oct-1 and HCF-1 (both
  cellular proteins)
• Significantly increases transcription of viral  genes

• Vhs (virion host shutoff) protein
   – This protein interacts with cellular proteins
   – Mediates degradation of both cellular and viral mRNAs
    – Degradation rate of viral is much lower compared to cellular,
      therefore they dominate
 Genes Set Stage For Viral DNA Replication

• HSV makes its own DNA polymerase
• 3 Replication Origins (2 oriS, oriL)
• Viral DNA is circularized
• UL9 binds ori S and unwind dsDNA, ICP8 helps in
  stabilizing ss DNA
• UL5, UL8 and UL52 (referred to as DNA helicase-primase
  complex) bind ss DNA and synthesize RNA primers
• UL30 (DNA polymerase) replicates DNA
• UL42 significantly enhances processivity
  Viral Genes Block Immune Response
• Out of 84 genes only 37 involved in replication
• Some of the remainder involved in blocking immune
  response against virus
• Vhs and ICP27 block interferon effects by degrading cellular
• ICP47 binds transporter proteins that aid antigen presentation
   – Self and viral peptides are constantly being presented thru MHC I and
     provoke immune responses when appropriate
   – ICP47 prevents transport of viral peptides on surface of cell
   –  no viral antigen presentation which means no immune response
Viral Genes Block Immune Response
                             HSV Latency

• Latency is typical in HSVs
• In case of infected neurons retrograde transport occurs and virus
  gains access to nucleus and can stay dormant for years
• Latency is attributed to
   – Limited amount of VP16 (viral tegument protein) enters nucleus
   –  No VP16 no  gene expression
• Neurons contain Luman and Zhangfei transcription factors
   – These transcription factors bind HCF-1 and inhibit formation of transcription
     complex Oct-1/HCF-1/VP16
• Only viral transcription that takes place is LAT’s (Latency
  associated transcripts)
Envelopment and Egress: 3 Possible Routes
    Envelopment and Egress: 3 Possible Routes
• HSV nucleocapsids are assembled in the nucleus
• It is thought that nuclear membrane is the source of the envelope
• Budding occurs from inner nuclear membrane to nuclear lumen
• Three theories are currently used to describe the transport from
nucleus to outside the cell
• One theory predicts that virions exit nucleus without envelope thru
nuclear pores (they enlarge to accommodate exit)
They gain envelops in the cytosol by mixing with fragmented
golgi fragments

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