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HERPES SIMPLEX VIRUS

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

Herpes Virus and Common Diseases
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Everybody knows chickenpox and likely you experienced the disease
as a child, can be dangerous when exposed to it in adulthood
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Another common ailment is lip and mouth “cold sores”
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Genital Herpes lesions caused by HSV, sexually transmitted
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HSV-1 cold sores (mild but annoying diseases)
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HSV-2 genital herpes
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Varicella zoster: chickenpox
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However the Herpes family is huge, over 100 members
HSV-1 Cold sore HSV-2 Genital Herpes

HSV Establishes Latent Infections
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Once infection has taken place HSV can remain dormant
for months, years, lifetime
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Cell types that HSV can infect and remain dormant
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Neurons, B-cells and T-cells
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Examples:
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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
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Enclosed in an envelope

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Capsid has icosahedral structure
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Capsid is bilayered
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Constructed from 6 proteins
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VP5 is the main one
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Envelope contains at least 10 different glycoproteins gB-gM
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Envelope also contains non-glycosylated proteins

HSV Entry Into Host Occurs Via Heparan Sulfate Proteoglycans
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gB and gC bind to host glycoproteins with heparan sulfate moieties (repeating
dissacharide: glucoronic and n-acetyl glucosamine)
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Following gB and gC is gD which binds to nectin1D
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OR HVEM (herpes virus entry mediator)
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Fusion occurs between viral envelope and host membrane
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Nucleocapsid is released into cytosol OR in acidified endosomes
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Transport to nuclear envelope occurs via µT and capsid interaction
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DNA is released into nucleus
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Capsid disintegrates
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Genome Expression in Nucleus
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Viral DNA is circularized once inside nucleus
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Viral DNA is localized in regions referred to as ND10
(nuclear domain 10)
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Viral genes transcribed by cellular RNA Poly II
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Gene expression divided into 4 groups
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Group α occurs within hours of viral infection (these genes
also referred to as “immediate early genes”)
∀
β genes (early genes) transcription occurs 4-8 hrs past
infection

β genes involved with viral DNA replication
∀
γ1 and γ2 (late genes) are the bulk of viral genes

Tegument Proteins
∀
α-TIF (a-trans-inducing factor) interacts w/Oct-1 and HCF-1 (both
cellular proteins)
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Significantly increases transcription of viral α genes
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Vhs (virion host shutoff) protein
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This protein interacts with cellular proteins
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Mediates degradation of both cellular and viral mRNAs
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Degradation rate of viral is much lower compared to cellular,
therefore they dominate

β Genes Set Stage For Viral DNA Replication
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HSV makes its own DNA polymerase
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3 Replication Origins (2 oriS, oriL)
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Viral DNA is circularized
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U
L
9 binds ori S and unwind dsDNA, ICP8 helps in
stabilizing ss DNA
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U
L
5, U
L
8 and U
L
52 (referred to as DNA helicase-primase
complex) bind ss DNA and synthesize RNA primers

•
U
L
30 (DNA polymerase) replicates DNA
•
U
L
42 significantly enhances processivity

Viral Genes Block Immune Response
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Out of 84 genes only 37 involved in replication
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Some of the remainder involved in blocking immune
response against virus
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Vhs and ICP27 block interferon effects by degrading cellular
mRNAs
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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
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Latency is typical in HSVs
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In case of infected neurons retrograde transport occurs and virus
gains access to nucleus and can stay dormant for years
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Latency is attributed to
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Limited amount of VP16 (viral tegument protein) enters nucleus

⇒ No VP16 no α gene expression
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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
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HSV nucleocapsids are assembled in the nucleus
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It is thought that nuclear membrane is the source of the envelope
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Budding occurs from inner nuclear membrane to nuclear lumen

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Three theories are currently used to describe the transport from
nucleus to outside the cell
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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