The Arenaviridae Family: Knowledge Gaps, Animal Models, Countermeasures, and Prototype Pathogens

Abstract

Lassa virus (LASV), Junin virus (JUNV), and several other members of the Arenaviridae family are capable of zoonotic transfer to humans and induction of severe viral hemorrhagic fevers. Despite the importance of arenaviruses as potential pandemic pathogens, numerous gaps exist in scientific knowledge pertaining to this diverse family, including gaps in understanding replication, immunosuppression, receptor usage, and elicitation of neutralizing antibody responses, that in turn complicates development of medical countermeasures. A further challenge to the development of medical countermeasures for arenaviruses is the requirement for use of animal models at high levels of biocontainment, where each model has distinct advantages and limitations depending on, availability of space, animals species-specific reagents, and most importantly the ability of the model to faithfully recapitulate human disease. Designation of LASV and JUNV as prototype pathogens can facilitate progress in addressing the public health challenges posed by members of this important virus family.

Keywords: animal models; arenaviruses; countermeasures; knowledge gaps; prototype pathogen.

Figure 1.

Phylogenetic relationships among species from the Arenaviridae family. Maximum-likelihood tree for L protein sequences representative of the genetic diversity within the Arenaviridae family. The phylogeny was inferred with the IQ-TREE software, using the LG + G4 model. Branch support was assessed using the ultrafast bootstrap approximation with 1000 replicates. Nodes with branch support >95% are indicated with circles. Tree leaves are according to the main groups within the family, namely the genera Hartmanivirus, Antennavirus, and Reptarenavirus, as well the new world complex and old world complex of the Mammarenavirus genus. These main groups are also shown by rectangles on the right part of the plot. For the new world complex, the main clades are indicated by their corresponding letters (A to D). For the Lassa virus species, lineages are indicated as part of the sequence name (*indicates that the lineage assignment is tentative).

Figure 2.

Arenavirus proteins and genomes. A, The arenavirus virion is enveloped and contains 2 or 3 RNA subunits, plus cellular ribosomes. B, Genome structures of the 4 genuses in the Arenaviridae family. X is a protein of unknown function encoded by antennaviruses. Plus symbol indicates that the gene is positive polarity. Negative symbol indicates the gene is negative polarity. Lines indicate proteins with significant sequence similarity.

Figure 3.

Structure and RNA binding of Lassa virus nucleoprotein (LASV NP). A, Cartoon representation of the N-terminal domain of LASV NP showing the deep groove through which the single-stranded RNA (ssRNA) channels. Conformational changes open and close the RNA-binding pocket. α-helix6 (α6) is positioned on top of the pocket, preventing RNA from binding. When α6 shifts away from the pocket as shown, the RNA gate opens to accommodate ssRNA. B, Cartoon representation of LASV NPΔ340, the C-terminal, immunosuppressive domain of LASV NP. Double-strand RNA (dsRNA), a potent interferon inducer, is degraded by the exonuclease activity of NP. Residues with similarity to the DEDD superfamily of exonucleases show coordination of a magnesium (Mg) ion. At the entrance to the active site of the exonuclease are several positively charged amino acids. Coordination of a zinc (Zn) ion is indicated.