Download Herpes Simplex Virus Lec. 7

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
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
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 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