The Viral Life Cycle

1. Attachment

Viral surface proteins recognise specific host cell-surface molecules. The receptor identity determines tissue tropism, host range, and (often) species barriers:

• SARS-CoV-2 spike → ACE2 (lung/gut epithelium); TMPRSS2 protease primes spike for fusion.
• Influenza HA → sialic acid: α-2,3 (avian intestine) vs α-2,6 (human upper respiratory tract). The receptor switch is the species barrier.
• HIV gp120 → CD4 + chemokine co-receptor (CCR5 or CXCR4). CCR5-Δ32 homozygotes are largely resistant.
• Rabies G → nicotinic acetylcholine receptor at neuromuscular junctions; explains the neurotropism.
• Polio VP1 → CD155 (PVR); humans are the only natural host.

2. Entry

Two main mechanisms (with overlap):

• Membrane fusion at the cell surface — HIV (gp41), measles (F), some strains of SARS-CoV-2 (S2). The fusion peptide inserts into the host membrane; conformational rearrangement (six-helix bundle, hairpin) brings the membranes together.
• Receptor-mediated endocytosis followed by fusion at low pH — influenza, dengue, most coronaviruses. The endosome acidifies, triggering HA conformational change and pH-dependent fusion-peptide exposure.
• Direct genome injection — tailed bacteriophages contract the tail sheath, drive a tube through the bacterial envelope, and inject the DNA without bringing the capsid inside.

3. Uncoating & Genome Localisation

Once inside, the genome must be released and brought to the right cellular location. RNA viruses replicate in the cytoplasm (with major exceptions: influenza, retroviruses use the nucleus). DNA viruses generally replicate in the nucleus (with major exception: poxviruses, which carry their own transcription machinery and replicate in the cytoplasm). Adenoviruses dock at the nuclear pore and inject their dsDNA directly through it.

4. Genome Replication & mRNA Synthesis

The Baltimore class predicts the strategy:

• (+)ssRNA (Group IV): genome is mRNA, immediately translated to make an RdRp, which copies the genome via a (−) intermediate.
• (−)ssRNA (Group V): genome is not mRNA. The virion must bring an RdRp inside to transcribe the (−) genome into (+) mRNA.
• dsRNA (Group III): RdRp inside core particles transcribes the dsRNA into (+) mRNA, which is exported. Replication occurs inside the core to keep dsRNA away from cytoplasmic dsRNA sensors.
• Retroviruses (Group VI): RNA genome → reverse-transcribed to dsDNA → integrated into the host chromosome → transcribed by host RNA polymerase II.
• DNA viruses: typically use host RNA polymerase II for transcription; replicate by viral or host DNA polymerases.

5. Assembly

Capsid proteins self-assemble around the genome. Some viruses package an already-formed empty capsid by ATP-driven motors (large dsDNA phages and herpesviruses use a portal-and-terminase mechanism that compresses dsDNA to near-crystalline density inside the head). Others co-assemble capsid and nucleic acid (TMV, hepatitis B). Enveloped viruses assemble at intracellular membranes (ER, Golgi) or at the plasma membrane, where matrix proteins (M1 in influenza, Gag in HIV) drive curvature and recruit envelope proteins.

6. Egress: Lysis vs Budding

Non-enveloped viruses generally lysethe cell — T4 phage uses lysin enzymes that punch through peptidoglycan; poliovirus permeabilises the membrane via 2B/3A. Enveloped viruses bud: the matrix protein deforms the membrane outward, ESCRT-III machinery scissions the bud, and progeny are released without (immediately) killing the cell. HIV buds from the plasma membrane; herpes from the inner nuclear membrane (then re-envelopes at the Golgi); influenza assembles at lipid rafts on the apical surface of polarised epithelia.

7. The One-Step Growth Curve

Synchronously infect a culture at high MOI (multiplicity of infection); count infectious progeny over time. The result: an eclipse phase (no infectious progeny; genome replicating, no assembled virions), then a rise phase (exponential accumulation), then a plateau (cells have lysed or stopped). Eclipse durations: ~20 min for T4, ~6 h for poliovirus, ~10 h for influenza, ~24 h for HIV. Burst sizes range from ~50 (HIV) to ~1000 (T4) to ~10⁵ (poliovirus per cell). The one-step curve is the basic experimental tool of virology.