← Back

Module 3 · RNA Viruses

RNA Viruses

RNA viruses are responsible for nearly every recent pandemic and a large fraction of chronic disease. Their distinguishing feature is the RNA-dependent RNA polymerase (RdRp), an enzyme absent from uninfected animal cells — making it an excellent antiviral target. RdRps lack proofreading; mutation rates of 10−3 to 10−5 per base per replication cycle drive the quasispecies diversity that lets RNA viruses evade immunity, vaccines, and drugs.

1. (+)ssRNA Viruses (Group IV)

The genome is mRNA — ribosomes translate it on entry. The first translation products always include an RdRp.

  • SARS-CoV-2 (Coronaviridae): ~30 kb, the largest known RNA virus genome. Produces a single polyprotein cleaved by viral proteases (3CLpro and PLpro — targets of nirmatrelvir/Paxlovid). Famous for its proofreading nsp14 ExoN, which gives ~10× lower mutation rate than other RNA viruses and made the >30 kb genome possible.
  • Poliovirus (Picornaviridae): ~7.5 kb, single ORF, IRES-driven cap-independent translation, no envelope, T = 3 capsid. Wild-type poliovirus is now restricted to ~2 endemic countries (Afghanistan, Pakistan); the eradication campaign continues.
  • Hepatitis C virus (Flaviviridae): ~9.6 kb. Chronic infection in ~70 million people. Sofosbuvir (NS5B inhibitor) plus ledipasvir/velpatasvir (NS5A) gives >95% cure in 8–12 weeks — one of the great triumphs of antiviral pharmacology.
  • Dengue, Zika, West Nile, yellow fever, JEV (Flaviviridae): mosquito-borne; tropical and emerging in temperate regions with climate change. The dengue four-serotype problem makes vaccine development genuinely hard (antibody-dependent enhancement).
  • Norovirus (Caliciviridae): >90% of non-bacterial gastroenteritis outbreaks. Extremely low infectious dose (~10 virions).

2. (−)ssRNA Viruses (Group V)

The genome cannot be translated directly. Each virion packages an RdRp that, on entry, transcribes the (−) RNA into mRNA. The order of mRNAs reflects the order of genes on the genome (gradient of expression).

  • Influenza A (Orthomyxoviridae): segmented genome (8 segments). HA mediates sialic-acid binding and membrane fusion; NA cleaves sialic acid for release. Antigenic drift (point mutations) drives seasonal escape; antigenic shift (segment reassortment when two strains co-infect a host) produces pandemic strains (1918 H1N1, 1957 H2N2, 1968 H3N2, 2009 H1N1).
  • Rabies (Rhabdoviridae): bullet-shaped, ~12 kb, neurotropic, retrograde transport up motor neurons to the CNS. ~99% case-fatality once symptomatic; preventable by post-exposure vaccination + immunoglobulin.
  • Ebola, Marburg (Filoviridae): filamentous, ~19 kb, severe haemorrhagic fever, ~50–90% case fatality. mAbs (Inmazeb, Ebanga) and the rVSV-ZEBOV vaccine now exist.
  • Measles, mumps, RSV, parainfluenza (Paramyxoviridae): unsegmented, F + HN/H glycoproteins. Measles is the most contagious human pathogen (R0 ~12–18).

3. dsRNA Viruses (Group III)

Rotavirus (Reoviridae) is the major cause of severe paediatric diarrhoea worldwide; live-attenuated oral vaccines (Rotarix, RotaTeq) cut the burden dramatically since 2006. The 11-segment dsRNA genome stays inside the inner core throughout the replication cycle — (+) mRNAs are extruded through pores while dsRNA itself never enters the cytoplasm, avoiding triggering MDA5 or RIG-I dsRNA sensors.

4. Retroviruses (Group VI)

HIV-1 is the paradigmatic retrovirus. Cycle: gp120 binds CD4 and CCR5/CXCR4 → gp41-mediated fusion → capsid uncoating in the cytoplasm → reverse transcription (RT) of (+)RNA into dsDNA → nuclear import via the capsid through the nuclear pore → integration (integrase) into a transcriptionally active host gene → transcription by host RNA Pol II → mRNA export → translation → assembly at the plasma membrane → budding → protease cleavage of Gag/Gag-Pol matures the virion.

Each step is targeted by an FDA-approved drug class: NRTIs/NNRTIs (RT inhibitors), integrase strand-transfer inhibitors (raltegravir, dolutegravir, bictegravir), protease inhibitors (atazanavir, darunavir), entry inhibitors (maraviroc CCR5 antagonist; enfuvirtide gp41 fusion inhibitor). Combination antiretroviral therapy (cART) suppresses viral replication below detection and converts HIV from a fatal disease to a chronic one.

Retroviral integration explains a striking feature of mammalian genomes: ~8% of the human genome is composed of endogenous retroviruses (ERVs) — ancient germline integrations now fixed in the species. A few have been domesticated: syncytin-1 and syncytin-2, derived from retroviral envelope genes, are essential for placental development.

5. Mutation, Quasispecies & Error Catastrophe

RdRp error rates of ~10−4/base mean that for a 10 kb genome, every progeny carries ~1 mutation on average. A patient with HIV produces ~1010 virions/day — every possible single-base mutation occurs every day. Selection pressure (immune system, antivirals, vaccines) acts on this huge swarm; resistance emerges rapidly when only one drug is used.

Manfred Eigen’s 1971 quasispecies theory predicts an error catastrophe: above a critical mutation rate, even the best replicators cannot maintain genetic information. The antiviral favipiravir and (more famously) molnupiravir push polymerases past this edge by inducing lethal mutagenesis — a fundamentally new mode of antiviral action.

← Module 2Module 4 →