HERPES SIMPLEX VIRUS Characteristics of HSV DNA double

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 – VP 5 is the main one • Envelope contains at least 10 different glycoproteins g. B-g. M • Envelope also contains non-glycosylated proteins

HSV Entry Into Host Occurs Via Heparan Sulfate Proteoglycans • • g. B and g. C bind to host glycoproteins with heparan sulfate moieties (repeating dissacharide: glucoronic and n-acetyl glucosamine) Following g. B and g. C is g. D which binds to nectin 1 D 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 ND 10 (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 m. RNAs – 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 ori. S, ori. L) Viral DNA is circularized UL 9 binds ori S and unwind ds. DNA, ICP 8 helps in stabilizing ss DNA • UL 5, UL 8 and UL 52 (referred to as DNA helicase-primase complex) bind ss DNA and synthesize RNA primers • UL 30 (DNA polymerase) replicates DNA • UL 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 ICP 27 block interferon effects by degrading cellular m. RNAs • ICP 47 binds transporter proteins that aid antigen presentation – Self and viral peptides are constantly being presented thru MHC I and provoke immune responses when appropriate – ICP 47 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 VP 16 (viral tegument protein) enters nucleus – No VP 16 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/VP 16 • 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