Viral Attachment to the Host-Cell Receptor
trigger
Entry begins when surface glycoproteins on the virion bind the primary host-cell receptor, the committed first step that anchors the virus to the target cell. For HIV this is engagement of CD4 by the gp120 envelope; for HBV/HDV it is docking of the large surface protein at the NTCP bile-acid transporter on hepatocytes. This step is itself a drug target: attachment inhibitors block receptor binding — fostemsavir clamps gp120 so it cannot engage CD4, and the first-in-class peptide bulevirtide blocks HBV/HDV docking at NTCP. Because attachment depends on a virus- and host-specific receptor-binding interaction rather than a conserved enzyme, attachment inhibitors are exquisitely specific to a single virus.
Used by disorders
Hepatitis D
as HBsAg-Dependent Hepatocyte Entry via NTCP
Downstream
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Co-receptor Engagement
After primary-receptor attachment, viruses that require one engage a co-receptor to license fusion.
Show evidence (2 references)
"Entry of HIV into target cells is a complex, multi-stage process involving sequential attachment and CD4 binding, coreceptor binding, and membrane fusion."
Establishes attachment and CD4 binding as the committed first step of the ordered entry cascade modelled by this node. Evidence source is OTHER as this is a review article.
"Bulevirtide (BLV), a first-in-class entry inhibitor, is"
Phase III clinical trial identifying bulevirtide as a first-in-class entry inhibitor that blocks HBV/HDV docking at the NTCP receptor, the attachment-step drug action of this node. Evidence source is HUMAN_CLINICAL as this is a randomized clinical trial.
Co-receptor Engagement
effector
For viruses that require a second receptor, primary-receptor attachment is followed by engagement of a co-receptor that triggers the conformational changes licensing membrane fusion. The canonical example is HIV: after CD4 binding, gp120 engages a chemokine co-receptor — CCR5 or CXCR4 depending on viral tropism. This step is a distinct drug target: the CCR5 antagonist maraviroc occupies CCR5 and blocks the gp120–co-receptor interaction, but only against CCR5-tropic (R5) virus, making co-receptor antagonism inherently tropism-restricted.
Downstream
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Membrane Fusion and Delivery into the Cytoplasm
Co-receptor engagement drives the fusion glycoprotein conformational change that merges the viral and host membranes.
Show evidence (2 references)
"Maraviroc, a CCR5 antagonist, blocks interactions between the viral envelope proteins and the CCR5 coreceptor."
Pins the co-receptor-engagement step to its drug action — maraviroc blocks the viral envelope–CCR5 co-receptor interaction. Evidence source is OTHER as this is a review article.
"antagonists that prevent the entry of human immunodeficiency virus (HIV) into host CD4+ T cells by blocking the CCR5 co-receptor"
Confirms that CCR5 antagonists act at the co-receptor step, blocking the CCR5 co-receptor to prevent HIV entry into host CD4+ T cells. Evidence source is OTHER as this is a review article.
Membrane Fusion and Delivery into the Cytoplasm
therapeutic vulnerability
Receptor and co-receptor engagement trigger the fusion glycoprotein to drive merger of the viral envelope with a host membrane, delivering the viral genome into the cytoplasm. For HIV the gp41 transmembrane subunit refolds into a six-helix bundle that pulls the two membranes together; this conformational change is the committed, irreversible point of no return for entry. It is therefore the most-druggable entry step and the canonical conformance/treatment target of the module: the gp41 fusion inhibitor enfuvirtide binds the prehairpin intermediate and disrupts the conformational change that drives membrane fusion, arresting the cascade at its committed step. Attachment and co-receptor engagement are additional upstream drug targets, but membrane fusion is the step at which the genome would otherwise be irreversibly committed to the cytoplasm.
Downstream
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Suppression of Productive Viral Entry
Blocking membrane fusion prevents delivery of the genome into the cytoplasm, aborting productive entry.
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Tropism and Entry-Inhibitor Resistance
Virus- and tropism-specific surface proteins gate which entry step is druggable; a tropism switch or envelope mutation escapes the inhibitor.
Show evidence (1 reference)
"Enfuvirtide, a fusion inhibitor, disrupts conformational changes in gp41 that drive membrane fusion."
Pins the membrane-fusion step to its drug action — the fusion inhibitor enfuvirtide disrupts the gp41 conformational change that drives membrane fusion, the committed entry step and key conformance target of the module. Evidence source is OTHER as this is a review article.
Suppression of Productive Viral Entry
consequence
When an entry inhibitor engages attachment, co-receptor binding, or membrane fusion, the virus is prevented from delivering its genome into the cytoplasm, so productive infection of the target cell is aborted before any intracellular replication step. A co-receptor antagonist that occupies CCR5 prevents the gp120–co-receptor interaction; a fusion inhibitor that binds gp41 prevents the six-helix-bundle change required for membrane merger; an NTCP-blocking peptide prevents hepatocyte docking. This is the antiviral consequence of engaging the upstream entry-target steps — it sits upstream of, and independent from, every cytoplasmic drug target (polymerase, protease, integrase), which is why entry inhibitors combine with replication inhibitors without overlapping targets.
Show evidence (2 references)
"antagonists that prevent the entry of human immunodeficiency virus (HIV) into host CD4+ T cells by blocking the CCR5 co-receptor"
States the antiviral consequence of engaging an entry target — blocking the CCR5 co-receptor prevents HIV entry into host CD4+ T cells. Evidence source is OTHER as this is a review article.
"BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint"
Phase III evidence that entry inhibition (bulevirtide) produces a superior virologic/clinical outcome, the therapeutic endpoint of this consequence node. Evidence source is HUMAN_CLINICAL as this is a randomized clinical trial.
Tropism and Entry-Inhibitor Resistance
adaptive escape
Entry inhibition is the most narrowly gated antiviral strategy because the target is defined by viral tropism and receptor usage rather than a conserved enzyme. The clearest example is the HIV co-receptor antagonist maraviroc: it is active only against CCR5-tropic (R5) virus, so a viral population that uses or switches to the CXCR4 co-receptor (X4 tropism) is intrinsically unaffected, and a pre-treatment tropism assay is mandatory because a large fraction of treatment-experienced patients harbor CXCR4-using virus. Beyond tropism, resistance can arise from mutations in the V3 loop of the gp120 envelope that let the virus use the drug-bound co-receptor or shift co-receptor preference. This adaptive branch off the committed fusion node encodes why an entry inhibitor's target may not exist at all in a given virus, and why escape can occur without any change in the cytoplasmic replication machinery. Conforming entries can attach a treatment's tropism-restriction or failure mode to this node.
Show evidence (2 references)
"Resistance to maraviroc is low and mainly related to the presence of chemokine (C-X-C motif) receptor 4 (CXCR4) tropism HIV-1-infections or to mutations in the V3 region of glycoprotein (gp) 120"
Directly states the tropism- and envelope-mutation-based escape encoded by this node — maraviroc resistance is driven by CXCR4-tropic virus and gp120 V3 mutations. Evidence source is OTHER as this is a review article.
"As 50% or more of treatment-experienced patients may be infected with CXCR4-tropic virus, a tropism assay should be performed before initiating maraviroc therapy."
Confirms the tropism-gating principle: maraviroc is restricted to CCR5-tropic HIV, so a tropism assay is required because many patients carry CXCR4-tropic virus that the drug cannot reach. Evidence source is OTHER as this is a review article.