Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance

Abstract

Human rhinoviruses of the RV-C species are recently discovered pathogens with greater clinical significance than isolates in the RV-A+B species. The RV-C cannot be propagated in typical culture systems; so much of the virology is necessarily derivative, relying on comparative genomics, relative to the better studied RV-A+B. We developed a bioinformatics-based structural model for a C15 isolate. The model showed the VP1–3 capsid proteins retain their fundamental cores relative to the RV-A+B, but conserved, internal RV-C residues affect the shape and charge of the VP1 hydrophobic pocket that confers antiviral drug susceptibility. When predictions of the model were tested in organ cultures or ALI systems with recombinant C15 virus, there was a resistance to capsid-binding drugs, including pleconaril, BTA-188, WIN56291, WIN52035 and WIN52084. Unique to all RV-C, the model predicts conserved amino acids within the pocket and capsid surface pore leading to the pocket may correlate with this activity.

Early-life viral infections and the development of asthma

“…(48) As noted above, RV C species may be associated with the greatest burden of lower respiratory illness, and recent studies suggest that the structure of RV C may have led previously tested anti-virals to be ineffective for this particular species, which may have negatively impacted some of the studies of small molecules to date. (49) Future studies aimed at developing therapeutics toward RV-C are clearly a priority.…”

Atomic structure of a rhinovirus C, a virus species linked to severe childhood asthma

“…Additionally, Ile1198 and Tyr1246 partially block the entrance to the VP1 pocket. Therefore, as has been observed experimentally (14), no RV-Cs are likely to be responsive to antiviral therapies based on pocket-binding compounds.…”

“…3C and Table S2). These amino acids are conserved in almost all RV-Cs (14). Additionally, Ile1198 and Tyr1246 partially block the entrance to the VP1 pocket.…”

“…Only modeled structures, based on amino acid sequence comparisons, have been available to aid biological investigations (12)(13)(14)(15) However, with recent advances in direct electron detection (16) and image processing approaches (17,18), single-particle cryoelectron microscopy (cryo-EM) has now emerged as a powerful method for determining near atomic resolution (better than 4 Å) structures of macromolecular assemblies (19). Cryo-EM requires only a limited amount of sample without intensive purification, offering advantages over X-ray crystallography in structural studies of samples that are difficult to produce.…”

“…In many EVs, a hydrophobic pocket within the VP1 jelly roll and situated underneath the canyon floor is occupied by a fatty-acid like molecule, or "pocket factor" (23,24), that regulates the conformational states of the virus during cell entry (25). Capsidbinding reagents that replace the pocket factor within VP1 are effective antiviral therapeutics against many EVs (26), but not RV-Cs (14).…”