Arenavirus genetic diversity and its biological implications

Abstract

The Arenaviridae family currently comprises 22 viral species, each of them associated with a rodent species. This viral family is important both as tractable experimental model systems to study acute and persistent infections and as clinically important human pathogens. Arenaviruses are enveloped viruses with a bi-segmented negative-strand RNA genome. The interaction with the cellular receptor and subsequent entry into the host cell differs between Old World and New World arenavirus that use alpha-dystoglycan or human transferring receptor 1, respectively, as main receptors. The recent development of reverse genetic systems for several arenaviruses has facilitated progress in understanding the molecular biology and cell biology of this viral family, as well as opening new approaches for the development of novel strategies to combat human pathogenic arenaviruses. On the other hand, increased availability of genetic data has allowed more detailed studies on the phylogeny and evolution of arenaviruses. As with other riboviruses, arenaviruses exist as viral quasispecies, which allow virus adaptation to rapidly changing environments. The large number of different arenavirus host reservoirs and great genetic diversity among virus species provide the bases for the emergence of new arenaviruses potentially pathogenic for humans.

Fig. 1

Arenavirus virion structure and genome organization. Virions are spherical to pleomorphic, with a lipid membrane envelope, measuring 50–300 nm (average 110–130) in diameter. The virion contains two filamentous nucleocapsids per envelope, each with “strings of beads” appearance and helical symmetry (indicated in the figure with red circles). The viral glycoprotein (GP) forms trimers GP1/GP2 to form the spikes on the virus surface (blue in the figure). Each virion has two segments of linear ssRNA: L (large) (ca. 7.3 kb) and S (small) (ca. 3.5 kb). Both use an ambisense coding strategy to direct the synthesis of two polypeptides in opposite orientation, separated by a non-coding intergenic region (IGR) with a predicted folding of a stable hairpin structure. The S RNA encodes the viral glycoprotein precursor (GPC) and the nucleoprotein, NP. The L RNA encodes the viral RNA dependent RNA polymerase (RdRp, or L polymerase), and the small (ca. 11 kDa) RING finger protein Z. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Fig. 2

Arenavirus replication and transcription. The virus enters the cell via endosomal route. The viral uncoating in cytoplasm releases the viral genome. NP and L mRNAs (in the figure is shown the replication and transcription of S segment) are transcribed into genomic complementary mRNA, whereas the GP and Z are not translated from genomic species, but rather from genomic sense mRNAs that are transcribed using the corresponding antigenome RNA species, which also function as replicative intermediates. The primary transcription initiated at the genome promoter located at the genome 3′-end results in synthesis of NP mRNA from the S. Viral mRNA has a cap structure at the 5′-ends (green circle). Subsequently the virus polymerase can adopt a replicase mode and moves across of the IGR to generate a copy of the full-length antigenome RNA. This antigenome RNA will serve as template for the synthesis of the GP mRNA. The antigenome species serve also as templates for the amplification of the corresponding genome RNA species or replication. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Fig. 3

Phylogeny of the arenaviruses based on the analysis of the complete amino acid sequence of the nucleoprotein. Phylograms were obtained by using the tree reconstruction analysis of Treepuzzle 5.2 (Schmidt et al., 2002) with quartet puzzling algorithm (Strimmer and von Haeseler, 1996) and an accurate parameters estimation (quartet sampling for substitution process and NJ tree for rate variation) for both the model of substitution and the mixed model of heterogeneity (1 invariable + 8 gamma rates). The model of substitution, estimated from data set was the VT model (Muller and Vingron, 2000). The number of puzzling steps was set to 10,000 and the outgroup was LCMV Armstrong. The scale indicates the maximum likelihood branch length. Numbers represent support for the internal branches of the quartet puzzling tree topology in percent.