Treatment of highly virulent mammarenavirus infections-status quo and future directions

Abstract

Introduction: Mammarenaviruses are negative-sense bisegmented enveloped RNA viruses that are endemic in Africa, the Americas, and Europe. Several are highly virulent, causing acute human diseases associated with high case fatality rates, and are considered to be significant with respect to public health impact or bioterrorism threat.

Areas covered: This review summarizes the status quo of treatment development, starting with drugs that are in advanced stages of evaluation in early clinical trials, followed by promising candidate medical countermeasures emerging from bench analyses and investigational animal research.

Expert opinion: Specific therapeutic treatments for diseases caused by mammarenaviruses remain limited to the off-label use of ribavirin and transfusion of convalescent sera. Progress in identifying novel candidate medical countermeasures against mammarenavirus infection has been slow in part because of the biosafety and biosecurity requirements. However, novel methodologies and tools have enabled increasingly efficient high-throughput molecular screens of regulatory-agency-approved small-molecule drugs and led to the identification of several compounds that could be repurposed for the treatment of infection with several mammarenaviruses. Unfortunately, most of them have not yet been evaluated in vivo. The most promising treatment under development is a monoclonal antibody cocktail that is protective against multiple lineages of the Lassa virus in nonhuman primate disease models.

Keywords: Arenaviridae; Lassa; high-throughput; mammarenavirus; medical countermeasure; repurposing; small molecule; treatment.

Figure 1.. Mammarenavirus lifecycle.

(1) Mammarenavirions adsorb to cell-surface factors, followed by endocytic uptake and engagement of intracellular receptors; (2, 3) membrane fusion, uncoating, and release of S and L genomic RNP complexes into the cytosol; (4) transcription of viral subgenomic RNAs, translations of viral proteins NP, GPC, L, and Z, and genome replication via antigenomic intermediates (antigenomes); (5, 6) Z-mediated virion morphogenesis and budding. GP, glycoprotein complex; GP1, glycoprotein 1 subunit; GP2, glycoprotein 2 subunit; GPC, glycoprotein precursor; IGR, intergenic region; L, large; NP, nucleoprotein; RNP, ribonucleoprotein complex; S, small; Z, zinc-binding protein. Modified and updated from [2] as well as from [148] with permission of Taylor & Francis.