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HERPES SIMPLEX VIRUS... 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 d

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 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

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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