Aminoglycosides induce immune activation but is insufficient for systemic viral control: a double-blind...

Mucosally-applied aminoglycosides have demonstrated host-directed antiviral activity in preclinical models through induction of interferon-stimulated genes (ISGs). However, it remains unknown if systemically administered aminoglycosides elicit comparable effects in humans.

We conducted a single-centre randomized, double-blind, placebo-controlled trial in Singapore in 32 healthy adults who were randomized 1:1 using sequentially sealed envelopes, to receive single-dose intravenous gentamicin 5 mg/kg or placebo. Participants were subsequently challenged with live-attenuated yellow fever 17D (YF17D) virus and followed for 30 days. The primary outcome was the proportion of participants with detectable YF17D RNAemia. Secondary outcomes included RNAemia levels, symptom rates, neutralizing antibody titers, and innate immune transcriptomic changes.

We found no significant differences between the gentamicin and placebo groups in detectable RNAemia (62.5% [n = 10/16] vs. 68.8% [n = 11/16], p > 0.99), mean RNAemia levels (3.93 log₁₀ area under the curve [AUC] vs. 3.51 log₁₀ AUC, p = 0.81), symptom rates (56% [n = 9/16] vs. 25% [n = 4/16], p = 0.15) or antibody titers (mean log₁₀ PRNT₅₀ titer: 3.89 vs. 3.71, p = 0.37). However, transcriptomic profiling demonstrated upregulation of ISGs RSAD2 and OASL and the transcription factor IRF3 in gentamicin-treated individuals, with concomitantly higher protein expression of chemokines CCL2, CXCL12 and IL-27.

This study represents, to our knowledge, the first in humans to evaluate the host-directed antiviral effects of systemic aminoglycosides. Our findings suggest that, whilst modest and insufficient to control systemic viral infection, the immunomodulatory effects of aminoglycosides warrant continued exploration as a potential preventive strategy against mucosal viral infections.