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20 Cards in this Set
- Front
- Back
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HSV structure
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dsDNA virus
Linear Capsid Irregular tegument 12th vertex: different structure from 1-11; portal through which DNA enters and leaves capsid |
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Classification Herpes viruses
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Alpha: HSV1 and HSV2
Beta: CMV Gamma: EBV, Kaposi's sarcoma |
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Disease progression: Herpes
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Acute primary infection of epithelial cells: cytolytic replication; resolution by adaptive immunity (subclinical to mildly severe); neonates susceptible to more severe
Latency: retrograde migration to sensory neurons of DRG and TG Reactivation: trigger --> virus re-enters periphery (anterograde); not always symptomatic; more severe in immunosuppressed |
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HSV: types of pathogenesis
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Cell killing: due to replication within epithelial cells --> ulcerative skin lesions
Sepsis: robust systemic inflammatory response; unregulated cytokines --> mostly neonates Immune-mediated: reactivation and anterograde spread back to cornea --> neovascularization, leakage of neutrophils, cytokins, scarring (after virus cleared) |
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Epidemiology: HSV
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Not seasonal
Most infections (HSV1, VZV) occur by adolescence Transmission: VZV: respiratory droplets HSV: close contact: saliva, lesions, sex Many infections are asymptomatic |
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HSV replication and life cycle
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Immediate-early genes: regulatory
Early: DNA replication Late: structural genes Gains entry to mucosal epithelial cells (breaks in keratinized tissue) --> replicates and assembles in nucleus Parasitizes host but brings most machinery, including DdDNA pol Buds out of nucleus into ER lumen --> envelope fusion with membrane --> naked in cytoplasm --> golgi --> acquires final envelope --> buds out Glycoproteins on surface targets sensory neurons VZV dissemination: following infection, can enter nerve endings and T cells/lymphocytes --> organ systems --> other sensory neurons, DRG |
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HSV latency
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HSV1: lives in trigeminal ganglia
HSV2: lives in sacral ganglia VZV: DRG, TG Post-acute infection: retrograde axonal transport of nucleocapsids to neuronal cell bodies Limited acute replication and infection of additional neurons Stable maintenance of episomal DNA in nucleus No lytic gene expression |
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HSV maintenance of latency
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Intrinsic: epigenetic silencing- heterochromatin formation
Virus specific CD8 cells, perforin/granzyme pos. wait in vicinity of latent infection Viral non-coding RNAs: LATs, miRNA targets immediate-early genes of viral genome, silencing them |
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Reactivation: HSV
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Trigger: stress, sunlight, illness, immunosuppression
Anterograde spread back to periphery --> replication (re-entry into lytic phase) --> subclinical or clinical infections/shedding Rare retrograde spread from ganglion to CNS --> encephalitis |
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Primary acute infection: HSV1
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Gingivostomatitis (sores)
Pharyngitis with flu-like symptoms Genital symptoms rare Keritoconjunctivitis Cutaneous: herpetic Whitlow: cuts on hands - direct inoculation Herpes gladiatorum: skin lesions facilitated by trauma with wrestling |
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Primary acute infection: HSV2
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Almost always associated with clinical disease
Sores, painful urination, discharge Non-specific flu-like symptoms Latent: sacral ganglia |
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Acute HSV infection response
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Host epigenetic silencing: heterochromatin
PAMPS --> Expression IFN via TLRs--> antiviral state PKR: protein kinase; phosphorylates EIF2alpha involved in protein translation --> sacrifice host translation to stop viral translation Pro-inflammatory cytokines Evasion: reversal of epigenetic silencing, phosphorylation Immune expression viral peptides on MHCI Recruitment CD8+ Phagocytosis of cell debris Infected monocytes present MHCI and MHCII to CD8 and CD4 Evasion: glycoprotein E; used by virus to spread from cell to cell directly (doesn't have to go extracellularly) |
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Glycoprotein E: HSV
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Used by virus to spread from cell to cell
Doesn't have to go extracellularly Immune evasion |
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Reactivation: symptoms
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Cold sores, genital sores: heal more rapidly than primary infection
Recurrences remain in same area OR can be asymptomatic Typically more severe in immunocomp |
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Diagnosis of HSV
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Clinical lesions (physical exam)
Wound material: cytopathic effect on cell monolayer - forming plaques Characteristic giant cells, nuclear inclusions on microscopy Serology: ELISA to distinguish HSV1 from 2 |
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VZV: Primary disease
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Chicken pox
Mild systemic febrile illness with rash Incubation period is 3 weeks Lesions come in successive crops: macules, papules, vesicles, pustules, scab TM: respiratory droplets, direct contact |
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VZV: disseminated disease
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Disseminated disease: cervical, thoracic, lumbar, sacral ganglia
Initial replication in respiratory epithelium --> regional lymph nodes --> cell-associated viremia --> liver and spleen --> 2nd viremia --> transplant to skin and lungs --> infectious |
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ZVS secondary complications
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Secondary infections
Pneumonia Rare hemorrhagic varicella |
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Reactivated VZV
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Shinges (zoster)
Large coalesced lesions; dermatomal Only some neurons in a particular DRG Doesn't cross midline Complications: post-herpetic neuralgia |
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Treatment Herpes
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Acyclovir
Analog of guanosine, but no 3' hydroxyl Disrupts DNA synthesis Acyclovir incorporated into growing DNA chain but next nucleotide triphosphate can't be added Prodrug: must be triphosphorylated by viral thymidine kinase to be activated (only in infected cells) Highly effective Resistance: absence of decrease in viral TK --> conc not high enough to prevent chain termination In decreased viral TK, can use higher drug dose Foscarnet: for TK mutants Targets different part of DNA pol than acyclovir |
