27-Hydroxycholesterol inhibits rhinovirus replication in vitro and on human nasal and bronchial histocultures without selecting viral resistant variants

The genetic plasiticity of viruses is one of the main obstacles to the development of antivirals. The aim of this study has been to assess the ability of two physiologic oxysterols and host-targeting antivirals - namely 25- and 27-hydroxycholesterol (25OHC and 27OHC) - to select resistant strains, using human rhinovirus (HRV) as a challenging model of a viral quasispecies. Moreover, we selected 27OHC for further studies aimed at exploring its potential for the development of antiviral drugs. The results obtained with clonal or serial passage approaches show that 25OHC and 27OHC do not select HRV oxysterol-resistant variants. Moreover, we demonstrate the ability of 27OHC to inhibit the yield of HRV in 3D in vitro fully reconstituted human nasal and bronchial epithelia from cystic fibrosis patients and prevent virus-induced cilia damage. The promising antiviral activity of 27OHC and its competitive advantages over direct-acting antivirals, make this molecule a suitable candidate for further studies to explore its clinical potential.

Automated summary

The study assessed the ability of two physiologic oxysterols and host-targeting antivirals to select resistant strains and found that 25OHC and 27OHC did not select oxysterol-resistant variants. The results also demonstrated the antiviral activity of 27OHC in inhibiting HRV and preventing virus-induced cilia damage in vitro. The promising potential of 27OHC as an antiviral drug candidate was highlighted.