Lecture 1 Week 8

Lecture 1 Week 8

1. Genetic structure of a virus

   • Enveloped easily destroyed
   • Non-enveloped robust and stable

2. Components of virions

   • Envelope - host derived lipid membrane containing viral derived proteins
   • Tegument - amorphous protein layer (Herpes)/Matrix
   • Capsid - outer protective protein coat
   • Nucleocapsid - inner protective protein coat
   • Genome/nucleic acid
   • Accessory proteins
   • Outer protective layer that ediates binding and entry of virion
   • Nucleic acid/genome

3. Classification of viruses

   • Way they looked under EM (e.g. Small round viruses = norovirus)
   • Diseases they cause (e..g enteric virus)
   • The way they are transmitted (e.g. arboviruses)

4. Baltimore classification of viruses

   • Based on kind of genetic material in virus
   • mRNA as a central component of life

5. Generalities about viral genetics

   • small genomes
     • Herpes viruses 120-230 kb
   • HIV 9kb
   • Dengue 11kb

6. Generalities about viral genetics

   • Very little non-coding sequence
   • Overlapping reading frame
   • Translational read through
   • Alternative splicing
   • Co-ordinated expression

7. Genetic viral replication cycle

   • Binding and entry
   • Genome replication
     • mRNA production and protein translation
   • Viral mRNA transcription and protein translation
   • Assembly and release

8. Viral replication - binding and entry

   • Receptor-mediated
   • specific receptor
   • multiple receptors
   • non-specific binding e.g. glycans
   • target cell determined by
     • entry - presence of receptor or mechanisms for uptake
     • post-entry - replication determinants

9. Target cells and entry mechanisms

   • HIV - receptor mediated surface fusion and/or phagocytosis
   • CD4+ T cells monocytes/macrophages/dendritic cells
   • Heptitis C - receptor-mediated endocytosis
     • Hepatocytes
     • CD81, SRB-1, Claudin-1, Occludin
   • Influenza - receptor mediated endocytosis
     • Respiratory epithelium
     • Sialic acid - alpha, 2, 6, Galactose in humans, sialic acid alpha, 2-3-galactose in mice

10. Cell target can determine disease

    • Receptor usage determines sites of infection and disease outcome
    • CCR5 = macrophage tropic, slow, non-cytolytic infection (early stage disease)
    • CXCR4 = T-cell tropic rapid, cytolytic infection

11. Viral genome replication

    • DNA virus - DNA dependent DNA polymerase (DNA copied into DNA)
    • RNA virus - RNA dependent RNA polymerase (RNA copied into RNA)
    • Reverse transcribing viruses (retroviridae and hepadnaviruses)
    • RNA dependent DNA polymerase = reverse transcriptase

12. Viral Replication - mutation and diversity

    • DNA viruses
      • Stable genomes
      • Homologous and non-homologous recombination
    • RNA virus
      • Variable genomes
      • error-prone replication
      • Homologous and non-homogous
      • Quasispecies

13. Viral replication - transcription and translation

    • Prodction of mRNA using host cell enzymes, DNA dependent RNA polymerase (DNA viruses) or viral RdRpol (RNA viruses)
    • Processing, splicing
    • Transcriptional control via viral promoters (untranslated regions of genome)
    • Co-ordinated gene expression (Herpes)
    • Important point of control

14. Viral growth characeristics

    • Active infection: one virus in = many viruses out
    • Acute = infection quickly resolved
    • Latent = virus lies dormant with very little replication and can be re-activated
    • Chronic = persistent long term

15. Virus replication: assembly and release

    • Using host cellular pathways - Golgi secretion pahways
    • Cytolytic and destroys the cell (e.g. Rota virus)
    • Budding and release
      • From outer membrane
      • From internal vesicles
      • Creation of double membrane vesicles (e..g Herpesvirus, Rotavirus, Vaccina virus)

16. Viral diversity

    • One virus does not equal one genetic sequence
    • In the population = different serotypes and genotypes
    • In an individual person = quasispecies
    • Different subtypes within the population
      • E.g. 6 differnet HCV genotypes, influenza A and B, HN variants of influenza A
    • Quasispecies within the one patient
      • A swarm of virus sequences variations
      • Pool of genetic diversity
      • Most 'fit' virus = major virus species = consensus

17. Viral quasispecies and drug resistance

    • Quasispecies allow genetic diversity
      • Random mutation generates drug resistant variants
    • Drug resistant variants are selected by drug pressure = treatment failure within patient
    • Transmission of drug resistance = treatment failure within the population
    • HIV anti-retroviral therapy
    • Influenza, HCV

18. Viral quasispecies and immune evasion

    • Quasispecies allows genetic diversity
    • Randommuttions generates variants not recognised by primary antibody response
    • Variants are selected by immune pressure = viral immune escape within patient