This is an antiviral drug-mechanism module structured as a biological pathway, not a specific disease. Its nodes are successive biological steps of retroviral provirus establishment (reverse transcription of the viral RNA genome into cDNA -> integrase strand transfer into host chromatin -> establishment of the integrated provirus), with an antiviral consequence node (suppression of proviral integration) and an adaptive resistance branch; the INSTI drug class that acts on the strand-transfer step is described in the node text rather than modelled as a separate node. Disorder entries reference individual nodes via conforms_to (e.g., "viral_integrase_inhibition#Integrase Strand Transfer into Host Chromatin"), and their integrase-targeting treatments point at the inhibited node via target_mechanisms (analogous to how polymerase-targeting treatments link to a node in viral_polymerase_inhibition, and how cell-wall-active antibiotic treatments link to a node in bacterial_cell_wall_synthesis_inhibition). Key conformance / treatment target: "Integrase Strand Transfer into Host Chromatin" (the shared integrase target of all INSTIs). This module is retrovirus-specific: integration has no counterpart in non-retroviral antiviral targets, so the module is meaningless outside the retroviruses. It typically applies alongside viral_polymerase_inhibition (the reverse-transcriptase step is the trigger of this very cascade) and viral_protease_inhibition for a disease such as Acquired_Immunodeficiency_Syndrome, mirroring the multi-module antibacterial examples. The resistance node captures the gating knowledge that distinguishes "an INSTI is used" from durable suppression — integrase active-site mutations that mandate combination therapy and the use of high-barrier second-generation agents. See projects/ANTIVIRAL.md.
Reverse Transcription of the Viral RNA Genome into cDNA
trigger
Retroviral provirus establishment begins when the virally encoded reverse transcriptase copies the single-stranded viral RNA genome into a double-stranded linear DNA (cDNA). This reverse-transcribed cDNA is the obligate precursor of the integrated provirus: until it exists, there is nothing for integrase to insert. Reverse transcription therefore both precedes and licenses the integration step that this module targets, and is itself the target of the separate viral_polymerase_inhibition module (the nucleos(t)ide and non-nucleoside reverse-transcriptase inhibitors). This node is the trigger of the integration cascade rather than the INSTI drug target.
Downstream
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Integrase Strand Transfer into Host Chromatin
The double-stranded viral cDNA produced by reverse transcription is the substrate that integrase assembles with and inserts into the host genome.
Integrase Strand Transfer into Host Chromatin
therapeutic vulnerability
Once reverse transcription has produced the viral cDNA, the virally encoded integrase assembles with the cDNA ends into a nucleoprotein complex called the intasome and catalyzes two sequential reactions: 3'-processing, which trims the viral DNA termini, and strand transfer, which covalently inserts the processed 3' ends into host chromosomal DNA. This integrase is essential, conserved across the retroviruses, and absent from the host, making it a selectively exploitable drug target with no counterpart in non-retroviral antivirals. This is the central, most widely exploited node of the module and the canonical conformance / treatment target. The integrase strand-transfer inhibitors (INSTIs) — raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir — bind the intasome active site, chelate the two catalytic Mg2+ ions through an electronegative pharmacophore, displace the reactive 3' viral DNA end, and block the strand-transfer reaction. Because INSTIs engage the end of the viral DNA within the intasome, they inhibit the assembled complex but not free integrase.
Downstream
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Establishment of the Integrated Provirus
Successful strand transfer covalently inserts the viral cDNA into host chromatin, establishing the stable integrated provirus.
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Integrase Strand-Transfer Inhibitor Resistance
Drug pressure on the integrase active site selects strand-transfer inhibitor resistance mutations that reduce INSTI binding.
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Suppression of Proviral Integration
When strand transfer is pharmacologically blocked by an integrase strand-transfer inhibitor, no provirus is formed — the antiviral consequence of inhibiting this step.
Establishment of the Integrated Provirus
effector
Completion of strand transfer covalently inserts the reverse-transcribed viral cDNA into host chromosomal DNA, establishing the integrated provirus. The provirus is the committed, durable end-state of the cascade: it persists as a stable transcriptional template within the host genome and supports production of progeny virus, converting a transient infection into a permanent one. This is the effector node of the integration pathway — the biological outcome that INSTIs are deployed to prevent.
Suppression of Proviral Integration
consequence
When an INSTI engages the intasome and blocks strand transfer, the reverse-transcribed viral cDNA fails to integrate into host chromatin, so no provirus is established. The unintegrated viral DNA cannot serve as a durable transcriptional template and persists only as short-lived episomal forms (1-LTR and 2-LTR circles) before being degraded; clinically, adding an integrase inhibitor produces a measurable rise in these unintegrated 2-LTR circles, a direct readout that integration has been suppressed. This is the antiviral consequence of engaging the integrase target — analogous to chain termination in the polymerase module or autolysis in the cell-wall module — and aborts establishment of permanent infection in the target cell.
Integrase Strand-Transfer Inhibitor Resistance
adaptive escape
Like other antiretroviral targets, integrase is subject to drug-resistance selection. Replication under INSTI pressure selects integrase active-site substitutions that reduce inhibitor binding — most commonly the Y143, Q148 (often with the compensatory G140S/A), and N155 pathways for the first-generation agents raltegravir and elvitegravir. These mutations typically destabilize Mg2+ coordination or sterically perturb the active site. The second-generation INSTIs dolutegravir and bictegravir, with an expanded tricyclic scaffold, additional active-site contacts, and a much longer dissociative half-life, retain potency against most single-mutant variants and carry a high genetic barrier to resistance; in dolutegravir-based combination therapy, treatment-emergent integrase resistance is rare. This branch off the strand-transfer node explains why integrase-targeting monotherapy fails, why durable suppression relies on combination regimens and high-barrier second-generation agents, and why prior NRTI resistance and INSTI monotherapy raise the risk of dolutegravir failure. Conforming entries can attach a treatment's failure mode or combination rationale to this node.