RNA vs DNA Viral Genomes 2024 PDF

DNA versus RNA viral genomes The origin of virology Virus (sg.): venom, poisonous secretion of snakes/creatures/plants 1899 Martinus Beijerinck 1879, agricultural catastrophe in Netherlands Healthy plant...

DNA versus RNA viral genomes The origin of virology Virus (sg.): venom, poisonous secretion of snakes/creatures/plants 1899 Martinus Beijerinck 1879, agricultural catastrophe in Netherlands Healthy plant Mosaic tobacco virus 2 The puzzle of virus structure had a missing piece… Stanley, 1935 Bawden, 1936 Protein nature Ribonucleoprotein nature 3 Peter Medawar: ‘A virus is bad news wrapped up in protein’ What is the Darwinian goal of a virus? Reproductio n Different genomic flavors in the virus world RNA DNA Single Double Single Double stranded stranded stranded stranded Positive Negative stranded stranded SARS-CoV-2 Influenza virus Reovirus Parvovirus Papillomavirus HIV-1 Rabies virus Rotavirus Herpes simplex Hepatitis C virus Measles virus Smallpox Zika virus Rift valley fever virus Poliovirus If you were a virus, which kind of genome would you have, RNA or DNA?  Molecular differences of DNA and RNA? RNA… DNA… Uses uracil Uses thymine Typically single stranded Typically double stranded Nuclear and cytoplasmic Mainly nuclear OH at 2’ ribose position H at 2’ ribose position 8 Biological implications for viruses Intrinsic stability RNA DNA DNA RNA Long-term storage Short-term storage 9 Molecular implications of RNA and DNA Intrinsic stability RNA DNA Genome size RNA DNA 10 Molecular implications of RNA and DNA Intrinsic stability RNA DNA Genome size RNA DNA Polymerase fidelity and error correction RNA DNA 11 Quasispecies: viral genetic heterogenicity Normal Selective infection pressure Viral heterogenicity Dependent on mutation rate Viral fitness will drive selection Most mutations are neutral with no selection pressure Negative mutations are typically lost Positive mutations are selected Positive selection can change Mutation rate and positive selection through viral fitness are drivers of antigenic variation Average sequence 12 Mandary et al., MB, 2020 Mutation incidence and antigenic drift Prominent drift sites in IVA HA Antigenic drift is a stochastic process in which antigens accumulate small mutations. If any of these results advantageous, it will become predominant through selective pressure. Evolution of the SARS-CoV-2 spike N439K > early mutation enhances the binding affinity for the ACE2 receptor and reduces the neutralizing activity of some mAbs Y453F — associated with increased ACE2-binding affinity Δ69–70 was predicted to alter the conformation of an exposed NTD loop and was reported to be associated with increased infectivity Vaccination rises and ~90% of the plasma or serum neutralizing antibody activity targets the spike receptor- binding domain (RBD) E484K was identified as an escape mutation that emerges during exposure to mAbs C121 and C144. Multiple iterations: E484A, E484D, E484G and E484K S477G conferred resistance to two of the four sera tested. Multiple iterations: S477G, S477N and S477R 11-residue insertion in the NTD N5 loop between Y248 and L249, completely abolishing neutralization Escape mutations emerging in viruses exposed to convalescent plasma were identified in both the NTD (ΔF140, N148S, K150R, K150E, K150T, K150Q and S151P) and the RBD (K444R, K444N, K444Q, V445E and E484K) Harvey, Nat Rev Microb, 2021 Segmented viruses have a genome whose encoded genes are divided across two or more molecules of RNA/DNA. All of them should be incorporated into the viral particle for a virus to be infective. E.g. Influenza virus has a genome with 8 segments; Rift Valley fever virus has 3 segments. 16 Genome reassortment and antigenic shift Antigenic shift: major alteration in antigen sequence by a process of genome reassortment (segmented virus) or inter strain recombination. Examples in the next lecture!!! Recombination Recombination allows major alterations acquisition of new or functionally altered proteins through exchange of genetic material between viruses or with the host. If can lead to antigenic shift. Recombination during replication More frequent when the replication mechanism is discontinuous in RNA viruses or because the DNA repair mechanisms in DNA viruses. Podcast https://www.the-scientist.com/plenty-of-evidence-for-recombination-in-sars-cov-2-69156 Recombination: another process of genomic diversification Homologous Non- recombination homologous end joining recombination 20 Genetic storage capacity matters… RNA virus dsDNA virus Viral mimicry – stealing from the host Viral mimic receptor Immuno- modulator Receptor Receptor Signalling No Signal 22 LIR1 inhibitor, the CMV MHC-homolog UL18 CMV UL18 interacts with natural killer receptor LIR1 as a human MHC does Prevents activation of natural killers due to loss of MHCs in infected cells Yang et al., PNAS, 2008 Disabling the immune system with decoys Favoured by the large size of double stranded DNA viral genomes. Favoured by DNA-DNA host-virus recombination. Alcami, Nat Rev Imm 2003; Hernaez, et al., Cur. Op. Immunol., 2020 24 Absence of antigens - latency Viral RNA Viral DNA Long-lived nature of DNA allows long-lasting infections Lack of immune response to infected cells in latent state Impossibility to distinguish ectopic DNA from endogenous DNA in the nucleus Important clinical consequences: recurrent infections 25 RNA vs DNA viruses: conclusions RNA viruses have faster evolution capacity > rapid adaptation RNA viruses have plastic genomes to increase coding capacity > segmentation, polyproteins, splicing dsDNA viruses have grater storage capacity > broader protein arsenal dsDNA viruses are more stable and difficult to detect in the nucleus > persistent infections through latency Recommended reading… General virology books: "Viruses: A Very Short Introduction" by Dorothy H. Crawford “Principles of Virology" by S.J. Flint, et al "Fields Virology" edited by D.M. Knipe and P.M. Howley "Introduction to Modern Virology" by Nigel Dimmock and Andrew Easton Lay public oriented: “A planet of viruses” Carl Zimmer “Viruses: the invisible enemy” Dorthy Crawford “Viruses made easy: an easy to read guide on the foundations of viruses and virology”. Jon Adams Papers: “Impact of RNA Virus Evolution on Quasispecies Formation and Virulence” Mandary et al., 2019 “SARS-CoV-2 variant biology: immune escape, transmission and fitness” Harvey et al, 2023 “Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor” Yang et al 2018 “Virus-encoded cytokine and chemokine decoy receptors” Hernaez et al, 2020 “Molecular Aspects of Varicella-Zoster Virus Latency” Depledge et al., 2018 “Molecular Basis of Epstein–Barr Virus Latency Establishment and Lytic Reactivation” Murata et al, 2021 If you were a virus, which kind of genome would you have, RNA or DNA?