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HERPES SIMPLEX VIRUS

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
Zoster
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




http://www.dipartimentobiologia.it/doctoraltraining/campadelli.htm
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
infection
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
U
L
9 binds ori S and unwind dsDNA, ICP8 helps in
stabilizing ss DNA
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
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
mRNAs
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 LATs (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