Envelope Glycoprotein of Arenaviruses

Dominique J Burri,Antonella Pasquato,Stefan Kunz,Joel Ramos Palma

doi:10.3390/v4102162

Abstract

Arenaviruses include lethal human pathogens which pose serious public health threats. So far, no FDA approved vaccines are available against arenavirus infections, and therapeutic options are limited, making the identification of novel drug targets for the development of efficacious therapeutics an urgent need. Arenaviruses are comprised of two RNA genome segments and four proteins, the polymerase L, the envelope glycoprotein GP, the matrix protein Z, and the nucleoprotein NP. A crucial step in the arenavirus life-cycle is the biosynthesis and maturation of the GP precursor (GPC) by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) yielding a tripartite mature GP complex formed by GP1/GP2 and a stable signal peptide (SSP). GPC cleavage by SKI-1/S1P is crucial for fusion competence and incorporation of mature GP into nascent budding virion particles. In a first part of our review, we cover basic aspects and newer developments in the biosynthesis of arenavirus GP and its molecular interaction with SKI-1/S1P. A second part will then highlight the potential of SKI-1/S1P-mediated processing of arenavirus GPC as a novel target for therapeutic intervention to combat human pathogenic arenaviruses.

Highlights

Recent examples are Chapare virus, discovered in Bolivia, which is closely related to other South American arenaviruses [14], and Lujo virus, identified during a nosocomial outbreak of viral hemorrhagic fevers (VHF) with high mortality in Zambia and South Africa in 2008 that caused the death of four out of five patients [15]
The envelope glycoprotein of Arenaviruses is synthesized as a polypeptide composed of an Nterminal stable signal peptide (SSP) and the SSP-containing GP precursor (GPC)
To other enveloped viruses, whose GPs are processed by proprotein convertase (PC), such as HIV-1 and influenza virus, arenaviruses strictly rely on Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) for productive infection

Summary

Arenaviruses are important human pathogens

Arenaviruses are world-wide distributed negative strand RNA viruses that include a number of important human pathogens. Recent examples are Chapare virus, discovered in Bolivia, which is closely related to other South American arenaviruses [14], and Lujo virus, identified during a nosocomial outbreak of VHF with high mortality in Zambia and South Africa in 2008 that caused the death of four out of five patients [15]. The discovery of this virus represents the first new HF-associated arenavirus to be isolated and identified in Africa in nearly 40 years. Since 1970, there have been several cases of Lassa fever imported into Europe or North America [16]

Arenavirus life-cycle

The biosynthesis of the glycoprotein precursor

Targeting GPC maturation is a promising strategy against arenavirus infection

Findings

Role of the envelope glycoprotein on virus assembly and particle formation