Viral entry and fusion processes

Viral entry and fusion processes are the early steps by which viruses attach to host-cell receptors and deliver their genomes into the cytoplasm, typically via conformational changes in viral entry glycoproteins that drive membrane apposition and fusion pore formation for enveloped viruses.[2][4] For many enveloped viruses, proteolytic priming of metastable fusion proteins by host proteases (such as furin in producer or target cells, TMPRSS2 at the plasma membrane, or cathepsin L in endosomes) enables exposure of the fusion peptide and initiation of the merger between viral and cellular membranes.[3][5] Although fusion proteins across diverse virus families differ structurally, they converge on a common mechanism: receptor engagement and/or low pH triggers large-scale refolding that brings the two bilayers within nanometer proximity, proceeding through intermediates such as stalks and hemifusion diaphragms to a fusion pore through which the viral genome enters the cell.[2][4] HIV-1 entry exemplifies this paradigm: gp120 binds CD4 and a coreceptor (CCR5 or CXCR4), triggering gp41 refolding and formation of a six-helix bundle that drives membrane fusion; this step is druggable by fusion inhibitors.[1][4] SARS-CoV-2 entry similarly depends on the spike glycoprotein engaging ACE2, followed by S2′ cleavage by TMPRSS2 at the surface or cathepsin L in endosomes, releasing the fusion peptide to initiate pore formation; furin cleavage at S1–S2 in producer cells primes the spike and influences tropism.[3][5] Because these processes involve both viral proteins and host factors, therapeutics can target viral glycoproteins, host receptors/coreceptors, or host proteases that activate fusion.[1][3][4][5]

Other names

Viral membrane fusionVirus entryViral entry mechanismsViral fusion mechanismsMembrane fusion (viral)

Fusion peptide/gp41 inhibitors that prevent six-helix bundle formation and membrane merger (e.g., enfuvirtide inhibits HIV-1 Env-mediated fusion)[1][4] Receptor or coreceptor antagonists that block viral attachment/triggering (e.g., CCR5 antagonism prevents gp120–CCR5 engagement)[1] Protease inhibition that prevents activation (priming/cleavage) of viral fusion proteins (e.g., TMPRSS2 or cathepsin L inhibition for SARS-CoV-2 S2′ activation; furin-pathway targeting)[3][5] Neutralizing antibodies that block receptor-binding domains or fusion transitions of viral entry glycoproteins (general class across viruses)[3][4] Endosomal pH/trafficking modulators that impede low-pH-triggered fusion routes (class II/III fusion protein entry via endolysosomes)[2][4]