Viral Replication

Attachment. A viral surface protein, envelope glycoprotein in enveloped viruses or capsid protein in nonenveloped viruses, binds a specific host cell surface receptor. This is the single most important determinant of host range and tissue tropism. Receptor specificity explains why HIV specifically targets CD4-bearing cells, and why influenza haemagglutinin's receptor-binding specificity determines which host species and which respiratory tract region, upper versus lower, a given strain preferentially infects.

Entry. The process by which the virion, or its genome, crosses the host cell's outer membrane barrier, via one of three principal mechanisms.

Penetration. Sometimes used interchangeably with entry, and sometimes used to denote specifically the subsequent step of the viral genome or nucleocapsid crossing into the cytoplasm once the virion itself has entered the cell. The distinction is more terminological than practical.

Uncoating. The capsid is degraded, disassembled, or otherwise opened, releasing the viral genome into the cytoplasm or, for viruses replicating in the nucleus, allowing its subsequent transport there.

Genome replication. The viral genome is copied, using host polymerases, virus-encoded polymerases, or a combination of both. The specific enzymology and cellular location depend entirely on genome class.

Transcription. Production of viral mRNA from the genome. For positive-sense RNA viruses, this step is functionally bypassed, since the genome itself already serves directly as mRNA.

Translation. Viral mRNA is translated by host ribosomes into viral structural and nonstructural proteins. Since viruses possess no ribosomes of their own, this step is entirely and unavoidably host-dependent across every virus without exception, regardless of genome class.

Assembly. Newly synthesised genome copies and structural proteins self-assemble into new nucleocapsids, at a location within the cell determined by genome class, and for DNA viruses, generally corresponding to the site of genome replication itself.

Maturation. Final structural changes rendering the assembled particle infectious. This commonly involves virus-encoded protease-mediated cleavage of precursor structural proteins into their final, functional form, a step of major pharmacological significance since protease inhibitors specifically block this maturation step, producing noninfectious, structurally defective virions even when assembly itself has proceeded normally.

Release. New virions exit the cell via one of three principal mechanisms, completing the replication cycle.

Membrane fusion. The viral envelope fuses directly with the host cell plasma membrane, or, for some viruses, with an endosomal membrane following initial endocytic uptake, releasing the nucleocapsid directly into the cytoplasm. This mechanism requires an envelope and is mediated by specific fusion-competent envelope glycoproteins, examples including HIV gp41, influenza haemagglutinin following endosomal acidification, and the fusion glycoproteins of paramyxoviruses.

Endocytosis. The host cell engulfs the virion via its own normal endocytic machinery, often receptor-mediated endocytosis triggered by the initial attachment step, enclosing the virion within an endosome. Many viruses, both enveloped and nonenveloped, subsequently exploit endosomal acidification, a normal step in the endosome's maturation pathway, as a trigger for a conformational change in a viral protein.

This conformational change then mediates either membrane fusion, in enveloped viruses, releasing the nucleocapsid into the cytoplasm from within the endosome, or direct membrane disruption and pore formation in some nonenveloped viruses, achieving the equivalent functional outcome of genome release into the cytoplasm without possessing an envelope to fuse.

Direct penetration. The nucleic acid alone is injected directly through the host cell membrane, leaving the capsid outside the cell entirely. This is the characteristic entry mechanism of bacteriophages rather than a common mechanism among the human-pathogenic viruses that dominate clinical virology.

Budding is the characteristic release mechanism of enveloped viruses. The assembled nucleocapsid associates with a patch of host membrane already studded with viral glycoprotein, and the virion buds outward, acquiring its envelope directly from this host membrane in the process. Budding can occur without necessarily killing the host cell immediately, which allows some enveloped viruses to establish a more prolonged, chronic productive infection of a single cell, relevant to the persistent infection patterns seen in HIV, hepatitis B, and hepatitis C.

Cell lysis is the characteristic release mechanism of most nonenveloped viruses, which possess no mechanism for acquiring an envelope and instead accumulate within the cell until the cell itself ruptures, releasing all progeny virions simultaneously. This mechanism is inherently destructive to the host cell and is the direct structural basis of the cytopathic effects associated with many nonenveloped viruses.

Exocytosis is a release mechanism used by some enveloped viruses that assemble and acquire their envelope from an internal membrane compartment, the endoplasmic reticulum or Golgi apparatus, rather than the plasma membrane directly. The resulting enveloped virion is then transported to and released at the cell surface via the host cell's normal secretory pathway, a variant release strategy distinct from budding directly at the plasma membrane though sharing the same underlying envelope-acquisition principle.

Double-stranded DNA viruses generally replicate in the nucleus using host DNA polymerase, since DNA-templated DNA synthesis is chemically identical to normal host replication. These viruses depend heavily on the host cell's own replicative machinery, and several members of this group, notably herpesviruses and papillomaviruses, depend on the host cell being in, or being actively driven into, a replication-competent state resembling S-phase.

Single-stranded DNA viruses require synthesis of a complementary second strand before conventional transcription can proceed, since the genome exists only as a single strand within the virion. Parvovirus is the classic example.

Positive-sense RNA viruses carry a genome that is immediately translatable on entry, with no prior transcription required. Translation produces, among other proteins, an RNA-dependent RNA polymerase, which then synthesises a negative-sense intermediate copy, itself used as the template for producing further positive-sense genome copies and additional mRNA. Replication occurs entirely within the cytoplasm.

Negative-sense RNA viruses carry a genome that cannot be directly translated and requires the virion-packaged RNA-dependent RNA polymerase, present from the moment of entry since the host provides no equivalent enzyme, to first transcribe the genome into positive-sense mRNA. This same enzyme, or a related viral polymerase activity, subsequently produces new negative-sense genome copies using the positive-sense intermediate as template. Replication occurs predominantly in the cytoplasm, with influenza's nuclear replication as the recognised exception.

Retroviruses follow the most structurally distinctive replication pathway of any genome class. Virion-packaged reverse transcriptase copies the RNA genome into DNA, which is then integrated into the host chromosome by a second virion-packaged enzyme, integrase, becoming a permanent, heritable part of the host cell's own genome, the provirus, before any further viral gene expression can occur.