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
• high-throughput
• Lassa
• mammarenavirus
• medical countermeasure
• repurposing
• small molecule
• treatment

Article highlights

• Several mammarenaviruses can cause severe human diseases with high case fatality rates and hence are considered public health and bioterrorism threats.

• Therapeutic options for mammarenavirus infections and diseases remain highly limited and controversial.

• High-throughput screening of regulatory-agency-approved drugs for the treatment of a variety of diseases identified numerous molecules that could be ‘repurposed’ as medical countermeasures (MCMs) against mammarenaviruses.

• However, due to their classification as Risk Group 4 agents, further development of identified candidate MCMs has been slow and antiviral activity evaluation of identified candidates in animal models has rarely occurred.

• The most promising treatment under development is a cocktail consisting of three monoclonal antibodies that protects macaques against multiple lineages of Lassa virus even in advanced stages of disease.

List of abbreviations used in the manuscript

CB1	=	cannabinoid receptor 1
CD63	=	CD63 molecule
CHAPV	=	Chapare virus
DAG1	=	dystroglycan 1
dGTP	=	deoxyguanosine GTP
EC50	=	half-maximal response
ESCRT	=	endosomal sorting complex required for transport
FDA	=	U.S. Food and Drug Administration
FLEV	=	Flexal virus
GP	=	glycoprotein complex
GP1	=	glycoprotein subunit 1
GP2	=	glycoprotein subunit 2
GPC	=	glycoprotein precursor
GTOV	=	Guanarito virus
GTP	=	guanosine triphosphate
IC50	=	50% inhibitory concentration
IGR	=	intragenic region
JUNV	=	Junín virus
L	=	large
LAMP1	=	lysosomal-associated membrane protein 1
LASV	=	Lassa virus
LCMV	=	lymphocytic choriomeningitis virus
LUJV	=	Lujo virus
MACV	=	Machupo virus
MAPK	=	mitogen-activated protein kinase
MCM	=	medical countermeasure
NP	=	nucleoprotein
NRP2	=	neuropilin 2
ORF	=	open reading frame
R&D	=	research and development
RdRp	=	RNA-directed RNA polymerase
RNA	=	ribonucleic acid
RNP	=	ribonucleoprotein
S	=	small
S1P	=	site 1 protease
SBAV	=	Sabiá virus
SSP	=	stable signal peptide
TFRC	=	transferrin receptor 1
Z	=	zinc-binding protein

Acknowledgments

We would like to thank Fabian de Kok-Mercado and Jiro Wada (Integrated Research Facility at Fort Detrick) for creating/modifying Figure 1.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported in part through Laulima Government Solutions, LLC, prime contract with the National Institutes of Health National Institute of Allergy and Infectious Diseases under Contract No. HHSN272201800013C. IA Nunez, A Crane, and G Worwa performed this work as employees of Laulima Government Solutions, LLC. JH Kuhn performed this work as an employee of Tunnell Government Services, a subcontractor of Laulima Government Solutions, LLC, under Contract No. HHSN272201800013C. This work was also supported in part with federal funds from the NIH National Cancer Institute (NCI), under Contract No. 75N91019D00024. I Crozier performed this work as an employee of Leidos Biomedical Research, Inc., as supported by the Clinical Monitoring Research Program Directorate, Frederick National Lab for Cancer Research, sponsored by NCI. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of Health and Human Services or of the institutions and companies affiliated with the authors, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.