Abstract
Arenaviruses are a significant cause of hemorrhagic fever, an often-fatal disease for which there is no approved antiviral therapy. Lassa fever in particular generates high morbidity and mortality in West Africa, where the disease is endemic, and a recent outbreak in Nigeria was larger and more geographically diverse than usual. We are developing LHF-535, a small-molecule viral entry inhibitor that targets the arenavirus envelope glycoprotein, as a therapeutic candidate for Lassa fever and other hemorrhagic fevers of arenavirus origin. Using a lentiviral pseudotype infectivity assay, we determined that LHF-535 had sub-nanomolar potency against the viral envelope glycoproteins from all Lassa virus lineages, with the exception of the glycoprotein from the LP strain from lineage I, which was 100-fold less sensitive than that of other strains. This reduced sensitivity was mediated by a unique amino acid substitution, V434I, in the transmembrane domain of the envelope glycoprotein GP2 subunit. This position corresponds to the attenuation determinant of Candid#1, a live-attenuated Junín virus vaccine strain used to prevent Argentine hemorrhagic fever. Using a virus-yield reduction assay, we determined that LHF-535 potently inhibited Junín virus, but not Candid#1, and the Candid#1 attenuation determinant, F427I, regulated this difference in sensitivity. We also demonstrated that a daily oral dose of LHF-535 at 10 mg/kg protected mice from a lethal dose of Tacaribe virus. Serial passage of Tacaribe virus in LHF-535-treated Vero cells yielded viruses that were resistant to LHF-535, and the majority of drug-resistant viruses exhibited attenuated pathogenesis. These findings provide a framework for the clinical development of LHF-535 as a broad-spectrum inhibitor of arenavirus entry and provide an important context for monitoring the emergence of drug-resistant viruses.
Highlights
Targeting virulence factors is an intriguing antimicrobial strategy that may reduce selective pressure and delay or prevent emergence of antimicrobial resistance [1], but this approach has not been appreciably explored as an antiviral strategy
Lassa fever is a viral hemorrhagic fever disease that is transmitted to humans primarily through contact with the urine or feces of infected rodents
The disease is endemic in West Africa, and an unusually large outbreak occurred in Nigeria in early 2018
Summary
Targeting virulence factors is an intriguing antimicrobial strategy that may reduce selective pressure and delay or prevent emergence of antimicrobial resistance [1], but this approach has not been appreciably explored as an antiviral strategy. We provide here an example of an antiviral that suppresses viral replication in a manner regulated by amino acids within the viral envelope glycoprotein that contribute to virulence. The ramifications of this are a successful live vaccine strain that exhibits antiviral resistance and a tendency for drug-resistant variants to exhibit attenuation. One of the most frequently occurring VHFs, is caused by Lassa virus, a member of the family Arenaviridae [3] This family of enveloped RNA viruses is composed of snake (genera Reptarenavirus and Hartmanivirus) and rodent (genus Mammarenavirus) lineages [4, 5]; the rodent lineage is subdivided into Old World and New World viruses. There are four Lassa virus lineages with significant genetic diversity [8, 9], it has been proposed that a fifth lineage could be defined by subdividing lineage IV [10]
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