Effect of the AHR Inhibitor CH223191 as an Adjunct Treatment for Mammarenavirus Infections

TL;DR

This study explores using the AHR inhibitor CH223191 alongside favipiravir to treat mammarenavirus infections, showing promising antiviral effects in mice.

Contribution

The study demonstrates a novel synergistic antiviral combination using CH223191 and favipiravir against mammarenaviruses.

Findings

CH223191 combined with favipiravir showed synergistic antiviral effects in cell culture and mouse models.

The combination reduced weight loss and viral loads in AG129 mice infected with Tacaribe virus.

AHR inhibition is identified as a promising pharmacological target for developing new antivirals.

Abstract

The family Arenaviridae encompasses zoonotic, rodent-borne pathogens (e.g., Lassa, Machupo, and Junín viruses) that cause severe viral hemorrhagic fevers with high case fatality rates. The current therapeutic landscape is severely limited, underscoring the urgent need for novel antiviral strategies. A promising approach involves combining directly acting antivirals with host-targeted antivirals. A compelling host-targeted antiviral target is the aryl hydrocarbon receptor (AHR). This ubiquitous ligand-activated transcription factor is a recognized pro-viral host factor across multiple viral families. Building on prior work with Junín and Tacaribe viruses, we investigated whether the AHR inhibitor CH223191 could enhance the virus-directed antiviral activity of favipiravir against these viruses. First, we evaluated the toxicity and antiviral potential of CH223191 against a lethal Junín virus infection in male and female hTfR1 mice. After demonstrating substantial protection, we conducted preliminary assays to study the antiviral effects of combining CH223191 and favipiravir on Tacaribe virus (TCRV) infections in the Vero cell culture model. We observed synergistic interaction with all four models (ZIP, Loewe, Bliss, and HSA). We next determined the sub-optimal dose of favipiravir and conducted an antiviral combination study in the AG129 mouse model infected with TCRV. The combination effectively protected mice from a lethal TCRV infection and showed cooperative effects, reducing weight loss and viral loads. Overall, these results show that the AHR is a promising pharmacological target for the development of novel antivirals. Furthermore, we discovered a cooperative interaction between the activities of favipiravir and CH223191.

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