Virus and Host Mechanics Support Membrane Penetration and Cell Entry

Abstract

Viruses are quasi-inert macromolecular assemblies. Their metastable conformation changes during entry into cells, when chemical and mechanical host cues expose viral membrane-interacting proteins. This leads to membrane rupture or fusion and genome uncoating. Importantly, virions tune their physical properties and enhance penetration and uncoating. For example, influenza virus softens at low pH to uncoat. The stiffness and pressure of adenovirus control uncoating and membrane penetration. Virus and host mechanics thus present new opportunities for antiviral therapy.

FIG 1

Schematic depiction of virus and host mechanics with impact on virus entry into cells. (A) Proteolytic maturation during adenovirus progeny assembly increases internal pressure and, concomitantly, stiffness of the capsid coat (upper panel). (Lower panel) Acid exposure of influenza A virus during entry, e.g., leads to proton influx through the matrix protein 2 (M2) channel into the virion and reduces viral stiffness by enhancing rearrangement of internal proteins, including M1 and viral ribonucleoprotein particles (vRNPs) composed of viral RNA and nucleoprotein (NP). (B) Acto-myosin-mediated drifting motions of adenovirus bound to the coxsackievirus adenovirus receptor (CAR) and virus confinement by integrins on the cell surface lead to shedding of viral fibers, the first uncoating step in the viral disassembly program. (C) Incoming (fiberless) adenovirus binds to the nuclear pore complex (NPC) protein Nup214 by the major capsid protein hexon. The microtubule-dependent motor kinesin-1 (Kif5C heavy chain) attaches to the capsid by binding of its light chain Klc1/2 to protein IX (IX). Activation of the motor occurs upon heavy chain binding to Nup358 and initiates capsid disruption by displacement on microtubules, which may be tethered to the distal domain of Nup358. Concomitantly, capsid disruption removes Nup62 from the central channel structure of the NPC (but not Nup153 of the nuclear basket), and viral DNA is imported into the nucleus.