This pathogen-process-centric module models biological steps rather than individual drugs. Disorder nodes reference exact anchors with conforms_to, and protease-inhibitor treatments point to the conforming virus-specific processing node with target_mechanisms. Key conformance / treatment target: "Virus-Encoded Protease-Dependent Polyprotein Processing". The two outputs are deliberately distinct. COVID-19 and Hepatitis_C conform through "Replication-Complex Formation and Viral RNA Replication"; an HIV conformer would instead use "Protease-Driven Structural Virion Maturation" and may continue to "Production of Immature, Non-Infectious Virions". As a high-precision operational curation boundary, a qualifying branch must model synthesis of a viral polyprotein precursor, cleavage at defined junctions by a virus-encoded protease, and exactly the applicable productive output: nonstructural replicase function and viral RNA replication, or Gag/Gag-Pol structural maturation. Conformance to the central virus-encoded processing node is mandatory. Protease-resistance and immature-particle nodes are optional, context-specific extensions and are not sufficient by themselves. Host-protease entry or priming (including TMPRSS2 and furin), host CYP3A boosting, protease-mediated immune evasion without the polyprotein-processing trunk, replication or viremia alone, immature particles alone, and non-protease antiviral targets do not qualify. Ritonavir is itself an HIV protease inhibitor, but in modern regimens it is used almost exclusively as a pharmacokinetic enhancer. In nirmatrelvir/ritonavir it inhibits host CYP3A rather than the viral protease; that boosting role is therefore described separately from viral target inhibition and resistance. See projects/ANTIVIRAL.md.
Synthesis of the Viral Polyprotein Precursor
trigger
The viral genome is expressed as one or more polyprotein precursors. These precursors contain structural proteins, replicative enzymes, or both, and must be cleaved into individual functional products. Examples include HIV Gag and Gag-Pol, the HCV polyprotein, and the SARS-CoV-2 replicase polyproteins pp1a and pp1ab.
Used by disorders
COVID-19
as SARS-CoV-2 Replicase Polyprotein Translation (pp1a/pp1ab)
Downstream
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Virus-Encoded Protease-Dependent Polyprotein Processing
A virus-encoded protease cleaves the synthesized precursor at defined junctions to release functional viral proteins.
Show evidence (3 references)
"the Gag and GagPol polyproteins are translated"
This HIV-1 maturation review establishes synthesis of Gag and Gag-Pol as the upstream source of protease substrates.
"After viral entry, two overlapping polyproteins, pp1a (490 kDa) and pp1ab (794 kDa), are translated by the translational machinery of the host."
The SARS-CoV-2 structural study identifies translation of pp1a and pp1ab as the precursor-producing step upstream of Mpro processing.
"The hepatitis C virus (HCV) genome encodes a long polyprotein, which is processed by host cell and viral proteases to the individual structural and non-structural (NS) proteins."
The primary HCV cleavage-assay study establishes the long polyprotein precursor and its subsequent proteolytic processing.
Virus-Encoded Protease-Dependent Polyprotein Processing
therapeutic vulnerability
A virus-encoded peptidase cleaves the polyprotein precursor at defined sites. This shared druggable step is instantiated by HIV protease cleavage of Gag and Gag-Pol, HCV NS3/4A cleavage within the nonstructural region, and SARS-CoV-2 Mpro (3CLpro/nsp5) cleavage of pp1a and pp1ab. Active-site or substrate-cleft protease inhibitors prevent the applicable cleavage events. The products and downstream phenotype are branch-specific rather than interchangeable across these virus families.
Used by disorders
COVID-19
as SARS-CoV-2 Mpro-Dependent Processing of pp1a/pp1ab
Hepatitis C
as HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein
Downstream
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Replication-Complex Formation and Viral RNA Replication
In SARS-CoV-2 and HCV, processing releases nonstructural proteins required for replication-complex function and viral RNA replication.
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Protease-Driven Structural Virion Maturation
In HIV, Gag and Gag-Pol processing drives structural conversion of the nascent particle into a mature infectious virion.
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Protease-Inhibitor Resistance
Under inhibitor selection, protease substitutions that reduce drug binding while retaining sufficient processing activity can be enriched.
Show evidence (3 references)
"proteolytic processing of the Gag polyprotein by the viral protease"
The HIV-1 review supports protease-dependent Gag processing in the structural-maturation branch.
"Mpro of SARS-CoV-2 digests replicase polyproteins, releasing the nonstructural proteins (nsps)"
The SARS-CoV-2 structural study directly supports Mpro-dependent release of replicase nonstructural proteins.
"NS3/4A cleaves the polyprotein sequence at four specific regions."
The primary HCV cleavage-assay study directly supports NS3/4A-dependent polyprotein processing.
Protease-Driven Structural Virion Maturation
effector
In the structural-maturation branch exemplified by HIV-1, protease-mediated Gag and Gag-Pol cleavage reorganizes the immature particle and produces the mature capsid and other functional virion components. This branch is not used for SARS-CoV-2 Mpro or HCV NS3/4A conformances.
Downstream
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Production of Immature, Non-Infectious Virions
When structural Gag/Gag-Pol processing is inhibited, released HIV particles retain an immature, non-infectious phenotype.
Show evidence (2 references)
"the conversion of an immature, noninfectious particle to a mature infectious virion"
The HIV-1 review supports the protease-dependent immature-to-mature virion transition.
"the assembly of the mature conical capsid from fully processed capsid protein"
The HIV-1 review directly describes structural capsid maturation after proteolytic processing.
Production of Immature, Non-Infectious Virions
consequence
In the HIV structural-maturation branch, inhibiting viral protease prevents complete Gag and Gag-Pol cleavage. Particles can be released but retain immature architecture and are non-infectious. This consequence is scoped to the structural branch and is not asserted as the phenotype of HCV NS3/4A or SARS-CoV-2 Mpro inhibition.
Show evidence (1 reference)
"blocking the proteolytic cleavage of the Gag and GagPol polyprotein precursors, resulting in a defect in virus particle maturation"
The HIV-1 review directly supports defective particle maturation after protease inhibition.
Protease-Inhibitor Resistance
adaptive escape
Viral proteases can acquire substitutions that reduce inhibitor affinity while preserving enough catalytic activity for polyprotein processing. HCV NS3/4A resistance-associated substitutions at positions including R155, A156, and D168 illustrate this adaptive escape. Host-drug metabolism and pharmacokinetic boosting are intentionally excluded from this node: ritonavir or cobicistat enhancement changes inhibitor exposure, whereas resistance is a heritable viral target change selected under drug pressure.
Show evidence (2 references)
"three single amino acid residues (R155, A156 and D168) are notable for their presence in clinical isolates"
The computational HCV study identifies signature NS3/4A resistance positions observed in clinical isolates.
"the error-prone viral RNA polymerase causes the emergence of resistance"
The study supports the mutation supply from which protease-inhibitor resistance variants can be selected.