HERPES SIMPLEX VIRUS
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
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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 fragmentedgolgi fragments