The Middle East respiratory syndrome coronavirus (MERS‑CoV) uses dipeptidyl peptidase 4 (DPP4, also known as CD26) as its cellular receptor for entry. Soluble recombinant DPP4 (sDPP4) can block MERS‑CoV infection in cell culture and animal models, and endogenous soluble DPP4 in plasma has been proposed to reduce viral dissemination in infected individuals. The study summarized here examined whether MERS‑CoV can acquire resistance to sDPP4 and how such resistance would affect spike‑mediated entry.
The authors employed a vesicular stomatitis virus pseudotype system encoding the MERS‑CoV spike protein (VSV‑MERS‑S) to select for viral variants with reduced sensitivity to sDPP4. VSV‑MERS‑S was passaged in the presence of soluble recombinant DPP4 to drive selection of spike mutations. Subsequent analyses focused on mutations in the receptor‑binding domain (RBD) of the spike protein, evaluation of sDPP4 binding, and functional entry assays into cell lines expressing differential levels of DPP4.
Passaging VSV‑MERS‑S in the presence of sDPP4 resulted in selection of variants with amino acid substitutions at residue 507 of the spike RBD. Specifically, mutations L507I (leucine to isoleucine) and L507H (leucine to histidine) were identified as being selected under sDPP4 pressure.
The L507I and L507H substitutions reduced binding of the spike RBD to sDPP4. Functionally, these mutations conferred resistance to inhibition by sDPP4 in the VSV‑MERS‑S model system. Despite the reduction in sDPP4 binding, viruses carrying L507I or L507H retained robust entry into cell lines that express high levels of DPP4. In contrast, entry into cell lines with low DPP4 expression was reduced for these variants, indicating a context‑dependent effect on infectivity tied to receptor availability.
The authors also evaluated naturally occurring polymorphisms at the same residue that have been detected in MERS‑CoV sequences from patients: L507F, L507R, and L507P (phenylalanine, arginine, proline substitutions at position 507). These variants exhibited an even more pronounced phenotype than the experimentally selected substitutions. In particular, L507R and L507P conferred complete resistance to sDPP4 in the assay system used.
Collectively, the data demonstrate that substitutions at spike residue 507 can diminish binding to soluble DPP4 and thereby confer resistance to sDPP4 inhibition. Importantly, some of these substitutions are compatible with maintained entry into cells and tissues that express high levels of DPP4, suggesting that such variants could still support viral spread in DPP4‑rich environments despite being resistant to sDPP4.
These findings have two direct implications derived from the source material: first, therapeutic application of sDPP4 could select for escape variants with altered RBD residues (such as at L507); second, naturally occurring polymorphisms at L507 observed in patient sequences can have functional consequences for sDPP4 sensitivity.
The source did not report detailed in vivo fitness, clinical outcomes associated with these specific variants, or broader epidemiologic data on the prevalence and transmission dynamics of L507 variants beyond noting their detection in patient sequences. Those aspects were therefore not addressed in this report.
Mutations at spike residue 507 (L507I/H) emerged during in vitro selection with sDPP4 and reduced sDPP4 binding.
These mutations conferred resistance to sDPP4 while preserving efficient entry into cells with high DPP4 expression; entry into low‑DPP4 cells was impaired.
Naturally occurring L507 polymorphisms (L507F/R/P) from patient isolates showed stronger resistance phenotypes, with L507R and L507P producing complete sDPP4 resistance in the model.
The study underscores a potential mechanism by which decreased receptor binding can enable escape from a soluble receptor‑based inhibitor while remaining compatible with infection of tissues that present abundant receptor.
The source focused on in vitro selection and entry assays using a VSV pseudotype system. It did not provide in vivo efficacy data for sDPP4 against emergent variants, nor clinical correlations between L507 polymorphisms and patient outcomes. Such data were not reported and therefore are outside the scope of this summary.