Formation of rhinovirus-soluble ICAM-1 complexes and conformational changes in the virion

Abstract

Viral receptors serve both to target viruses to specific cell types and to actively promote the entry of bound virus into cells. Human rhinoviruses (HRVs) can form complexes in vitro with a truncated soluble form of the HRV cell surface receptor, ICAM-1. These complexes appear to be stoichiometric, with approximately 60 ICAM molecules bound per virion or 1 ICAM-1 molecule per icosahedral face of the capsid. The complex can have two fates, either dissociating to yield free virus and free ICAM-1 or uncoating to break down to an 80S empty capsid which has released VP4, viral RNA, and ICAM-1. This uncoating in vitro mimics the uncoating of virus during infection of cells. The stability of the virus-receptor complex is dependent on temperature and the rhinovirus serotype. HRV serotype 14 (HRV14)-ICAM-1 complexes rapidly uncoat, HRV16 forms a stable virus-ICAM complex which does not uncoat detectably at 34 degrees C, and HRV3 has an intermediate phenotype. Rhinovirus can also uncoat after exposure to mildly acidic pH. The sensitivities of individual rhinovirus serotypes to ICAM-1-mediated virus uncoating do not correlate with uncoating promoted by incubation at low pH, suggesting that these two means of virus destabilization occur by different mechanisms. Soluble ICAM-1 and low pH do not act synergistically to promote uncoating. The rate of uncoating does appear to be inversely related to virus affinity for its receptor.

Picornavirus inhibitors

“…Large amounts of truncated ICAM-1 lacking the hydrophobic and cytoplasmic domains have been obtained (Marlin et al, 1990). These truncated forms are soluble and interact with rhinovirus particles (Marlin et al, 1990;Hoover-Litty and Greve, 1993;Olson et al, 1993a). The structure of the truncated ICAM-I complexed with rhinovirus particles has been determined using cryoelectron microscopy, indicating that the receptor binds into the canyon (Olson et al, 1993a, b).…”

“…The binding of virion particles to their receptors induces conformational changes in some virion proteins that could trigger the interaction of these proteins with the membrane (Fricks and Hogle, 1990;Hoover-Litty and Greve, 1993). Subsequently, the translocating activity of some of the virion proteins will be put in motion, thus inducing the passage of the virion through the lipid bilayer P6rez and Carrasco, 1993).…”

“…In the model indicated above, receptor molecules are regarded as playing an active role during virus entry (Fricks and Hogle, 1990;Carrasco et al, 1993;Hoover-Litty and Greve, 1993). The receptor binds the particle to the cell surface and this binding induces, in the virions, conformational changes that are required to uncoat the virion particle (Moore et al, 1990;Hoover-Litty and Greve, 1993) (see Section 2.3). This process is required to allow penetration of the membrane and entry to the cytoplasm (Fricks and Hogle, 1990;Hoover-Litty and Greve, 1993).…”

“…The receptor binds the particle to the cell surface and this binding induces, in the virions, conformational changes that are required to uncoat the virion particle (Moore et al, 1990;Hoover-Litty and Greve, 1993) (see Section 2.3). This process is required to allow penetration of the membrane and entry to the cytoplasm (Fricks and Hogle, 1990;Hoover-Litty and Greve, 1993). In agreement with this is the finding that binding of opsonized poliovirus to mouse L cells does not lead to infection (Mason et al, 1993), indicating that the simple attachment of poliovirus to the cell surface does not suffice to initiate infection.…”

“…Alternatively, energy may be required in the form of ATP, or as the proton-motive (membrane potential and/or pH gradient) generated in endosomes by the activity of the proton-ATPase pump, that could be used to drive the nucleocapsid through the lipid barrier of the membrane . A simple mechanistic model of viral particles opening pores in the membrane through which the genome passes is, however, inconsistent with the fact that the uncoating per se can occur in vitro in the presence of receptors (Hoover-Litty and Greve, 1993), whereas the entry of the genome into the cytoplasm requires a metabolically active cell (Hoekstra and Kok, 1989;Marsh and Helenius, 1989). The presence of ion channels in icosahedral virus particles (Kalko et al, 1992) may indicate that insertion of these capsids into membranes opens the ion channels that are required to dissipate the ionic gradients between endosomes and the cytoplasm.…”