Arenavirus Quasispecies and Their Biological Implications

Abstract

The family Arenaviridae currently comprises over 20 viral species, each of them associated with a main rodent species as the natural reservoir and in one case possibly phyllostomid bats. Moreover, recent findings have documented a divergent group of arenaviruses in captive alethinophidian snakes. Human infections occur through mucosal exposure to aerosols or by direct contact of abraded skin with infectious materials. Arenaviruses merit interest both as highly tractable experimental model systems to study acute and persistent infections and as clinically important human pathogens including Lassa (LASV) and Junin (JUNV) viruses, the causative agents of Lassa and Argentine hemorrhagic fevers (AHFs), respectively, for which there are no FDA-licensed vaccines, and current therapy is limited to an off-label use of ribavirin (Rib) that has significant limitations. Arenaviruses are enveloped viruses with a bi-segmented negative strand (NS) RNA genome. Each genome segment, L (ca 7.3 kb) and S (ca 3.5 kb), uses an ambisense coding strategy to direct the synthesis of two polypeptides in opposite orientation, separated by a noncoding intergenic region (IGR). The S genomic RNA encodes the virus nucleoprotein (NP) and the precursor (GPC) of the virus surface glycoprotein that mediates virus receptor recognition and cell entry via endocytosis. The L genome RNA encodes the viral RNA-dependent RNA polymerase (RdRp, or L polymerase) and the small (ca 11 kDa) RING finger protein Z that has functions of a bona fide matrix protein including directing virus budding. Arenaviruses were thought to be relatively stable genetically with intra- and interspecies amino acid sequence identities of 90-95 % and 44-63 %, respectively. However, recent evidence has documented extensive arenavirus genetic variability in the field. Moreover, dramatic phenotypic differences have been documented among closely related LCMV isolates. These data provide strong evidence of viral quasispecies involvement in arenavirus adaptability and pathogenesis. Here, we will review several aspects of the molecular biology of arenaviruses, phylogeny and evolution, and quasispecies dynamics of arenavirus populations for a better understanding of arenavirus pathogenesis, as well as for the development of novel antiviral strategies to combat arenavirus infections.

Ancient Evolution of Mammarenaviruses: Adaptation via Changes in the L Protein and No Evidence for Host–Virus Codivergence

“…Filtered alignments did not show substantial substitution saturation ( supplementary table S4 , Supplementary Material online) and no evidence of recombination. Previous studies indicated that recombination events at the 3′ end of GPC occurred in the ancestor of Northern American NW viruses ( Grande-Pérez et al. 2016 ).…”

Identification of phlebovirus and arenavirus RNA sequences that stall and repress the exoribonuclease XRN1

“…The N mRNA is a major transcript made from the ambisense S segment of the RVFV/phlebovirus genome. Because viral ambisense RNA segments often contain large intergenic structures that presumably aid in the generation of mRNAs (30,31), we wished to determine whether RNAs from other viruses that use the ambisense approach to gene expression also stall XRN1 as part of their strategy for host interaction. Arenaviruses have a bipartite genome and use an ambisense approach to generate mRNAs from both the genomic and anti-genomic version of both segments (Fig.…”

Epistastic Interactions within the Junín Virus Envelope Glycoprotein Complex Provide an Evolutionary Barrier to Reversion in the Live-Attenuated Candid#1 Vaccine

“…As an RNA virus, Candid#1 exists as a quasispecies that contains genetic variants that have been shown to give rise to clonal isolates of differing virulence (30,31). Nonetheless, the attenuated phenotype of Candid#1 appears to be stable in research laboratories and throughout its limited use as a vaccine.…”