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Experimental Biology and Medicine... Oct 2023, or Sabiá virus (SABV), is a New World (NW) arenavirus associated with fulminant hemorrhagic disease in humans and the sole biosafety level 4 microorganism ever... (Review)
Review
, or Sabiá virus (SABV), is a New World (NW) arenavirus associated with fulminant hemorrhagic disease in humans and the sole biosafety level 4 microorganism ever isolated in Brazil. Since the isolation of SABV in the 1990s, studies on viral biology have been scarce, with no available countermeasures against SABV infection or disease. Here we provide a comprehensive review of SABV biology, including key aspects of SABV replication, and comparisons with related Old World and NW arenaviruses. SABV is most likely a rodent-borne virus, transmitted to humans, through exposure to urine and feces in peri-urban areas. Using protein structure prediction methods and alignments, we analyzed shared and unique features of SABV proteins (GPC, NP, Z, and L) that could be explored in search of therapeutic strategies, including repurposing intended application against arenaviruses. Highly conserved catalytic activities present in L protein could be targeted for broad-acting antiviral activity among arenaviruses, while protein-protein interactions, such as those between L and the matrix protein Z, have evolved in NW arenaviruses and should be specific to SABV. The nucleoprotein (NP) also shares targetable interaction interfaces with L and Z and exhibits exonuclease activity in the C-terminal domain, which may be involved in multiple aspects of SABV replication. Envelope glycoproteins GP1 and GP2 have been explored in the development of promising cross-reactive neutralizing antibodies and vaccines, some of which could be repurposed for SABV. GP1 remains a challenging target in SABV as evolutive pressures render it the most variable viral protein in terms of both sequence and structure, while antiviral strategies targeting the Z protein remain to be validated. In conclusion, the prediction and analysis of protein structures should revolutionize research on viruses such as SABV by facilitating the rational design of countermeasures while reducing dependence on sophisticated laboratory infrastructure for experimental validation.
Topics: Humans; Arenaviruses, New World; Viral Proteins; Arenaviridae Infections; Antiviral Agents; Molecular Biology
PubMed: 37937408
DOI: 10.1177/15353702231199071 -
Current Topics in Microbiology and... 2016The 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... (Review)
Review
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.
Topics: Animals; Antiviral Agents; Arenaviridae Infections; Arenavirus; Evolution, Molecular; Genetic Variation; Genome, Viral; Humans; Phylogeny; Virus Replication
PubMed: 26472215
DOI: 10.1007/82_2015_468 -
Viruses Oct 2012Arenaviruses include lethal human pathogens which pose serious public health threats. So far, no FDA approved vaccines are available against arenavirus infections, and... (Review)
Review
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.
Topics: Amino Acid Sequence; Antiviral Agents; Arenaviridae Infections; Arenavirus; Glycosylation; Golgi Apparatus; Humans; Proprotein Convertases; Protein Sorting Signals; Proteolysis; Pyrrolidines; Receptors, Cell Surface; Serine Endopeptidases; Viral Envelope Proteins; Virus Assembly; Virus Attachment
PubMed: 23202458
DOI: 10.3390/v4102162 -
Clinical Microbiology and Infection :... Apr 2019Viral haemorrhagic fever can be caused by one of a diverse group of viruses that come from four different families of RNA viruses. Disease severity can vary from mild... (Review)
Review
Viral haemorrhagic fever can be caused by one of a diverse group of viruses that come from four different families of RNA viruses. Disease severity can vary from mild self-limiting febrile illness to severe disease characterized by high fever, high-level viraemia, increased vascular permeability that can progress to shock, multi-organ failure and death. Despite the urgent need, effective treatments and preventative vaccines are currently lacking for the majority of these viruses. A number of factors preclude the effective study of these diseases in humans including the high virulence of the agents involved, the sporadic nature of outbreaks of these viruses, which are typically in geographically isolated areas with underserviced diagnostic capabilities, and the requirements for high level bio-containment. As a result, animal models that accurately mimic human disease are essential for advancing our understanding of the pathogenesis of viral haemorrhagic fevers. Moreover, animal models for viral haemorrhagic fevers are necessary to test vaccines and therapeutic intervention strategies. Here, we present an overview of the animal models that have been established for each of the haemorrhagic fever viruses and identify which aspects of human disease are modelled. Furthermore, we discuss how experimental design considerations, such as choice of species and virus strain as well as route and dose of inoculation, have an influence on animal model development. We also bring attention to some of the pitfalls that need to be avoided when extrapolating results from animal models.
Topics: Animals; Arenaviridae; Bunyaviridae; Disease Models, Animal; Filoviridae; Flaviviridae; Hemorrhagic Fevers, Viral; Humans
PubMed: 24690109
DOI: 10.1111/1469-0691.12630 -
Expert Review of Vaccines 2024
Topics: Humans; Vaccines; Virus Replication; Lassa virus; Lassa Fever; Arenaviridae Infections
PubMed: 38044877
DOI: 10.1080/14760584.2023.2290683 -
Current Opinion in Virology Jun 2016Surface glycoproteins direct cellular targeting, attachment, and membrane fusion of arenaviruses and are the primary target for neutralizing antibodies. Despite... (Review)
Review
Surface glycoproteins direct cellular targeting, attachment, and membrane fusion of arenaviruses and are the primary target for neutralizing antibodies. Despite significant conservation of the glycoprotein architecture across the arenavirus family, there is considerable variation in the molecular recognition mechanisms used during host cell entry. We review recent progress in dissecting these infection events and describe how arenaviral glycoproteins can be targeted by small-molecule antivirals, the natural immune response, and immunoglobulin-based therapeutics. Arenaviral glycoprotein-mediated assembly and infection pathways present numerous opportunities and challenges for therapeutic intervention.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Antiviral Agents; Arenaviridae Infections; Arenavirus; Humans; Membrane Fusion; Membrane Glycoproteins; Mice; Viral Envelope Proteins; Viral Vaccines; Virus Internalization
PubMed: 27104809
DOI: 10.1016/j.coviro.2016.04.001 -
FEBS Open Bio Apr 2021Arenaviruses are enveloped viruses containing a segmented, negative, and ambisense single-stranded RNA genome wrapped with a nucleoprotein (NP). The NP is the most...
Arenaviruses are enveloped viruses containing a segmented, negative, and ambisense single-stranded RNA genome wrapped with a nucleoprotein (NP). The NP is the most abundant viral protein in infected cells and plays a critical role in both replication/transcription and virion assembly. The NP associates with RNA to form a ribonucleoprotein (RNP) complex, and this implies self-assembly while the exact structure of this polymer is not yet known. Here, we report a measurement of the full-length Mopeia virus NP by negative stain transmission electron microscopy. We observed RNP complex particles with diameter 15 ± 1 nm as well as symmetric circular heptamers of the same diameter, consistent with previous observations.
Topics: Amino Acid Sequence; Arenavirus; Models, Molecular; Nucleoproteins; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; RNA-Binding Proteins; Recombinant Proteins; Viral Proteins
PubMed: 33534950
DOI: 10.1002/2211-5463.13106 -
Virologica Sinica Oct 2016Mammarenaviruses, including lethal pathogens such as Lassa virus and Junín virus, can cause severe hemorrhagic fever in humans. Entry is a key step for virus infection,... (Review)
Review
Mammarenaviruses, including lethal pathogens such as Lassa virus and Junín virus, can cause severe hemorrhagic fever in humans. Entry is a key step for virus infection, which starts with binding of the envelope glycoprotein (GP) to receptors on target cells and subsequent fusion of the virus with target cell membranes. The GP precursor is synthesized as a polypeptide, and maturation occurs by two cleavage events, yielding a tripartite GP complex (GPC) formed by a stable signal peptide (SSP), GP1 and GP2. The unique retained SSP interacts with GP2 and plays essential roles in virion maturation and infectivity. GP1 is responsible for binding to the cell receptor, and GP2 is a class I fusion protein. The native structure of the tripartite GPC is unknown. GPC is critical for the receptor binding, membrane fusion and neutralization antibody recognition. Elucidating the molecular mechanisms underlining the structure-function relationship of the three subunits is the key for understanding their function and can facilitate novel avenues for combating virus infections. This review summarizes the basic aspects and recent research of the structure-function relationship of the three subunits. We discuss the structural basis of the receptor-binding domain in GP1, the interaction between SSP and GP2 and its role in virion maturation and membrane fusion, as well as the mechanism by which glycosylation stabilizes the GPC structure and facilitates immune evasion. Understanding the molecular mechanisms involved in these aspects will contribute to the development of novel vaccines and treatment strategies against mammarenaviruses infection.
Topics: Animals; Arenaviridae; Arenaviridae Infections; Humans; Viral Envelope Proteins
PubMed: 27562602
DOI: 10.1007/s12250-016-3815-4 -
Nature Communications Sep 2023Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate....
Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate. We have designed and generated lipid nanoparticle encapsulated, modified mRNA vaccines that encode for the wild-type Lassa virus strain Josiah glycoprotein complex or the prefusion stabilized conformation of the Lassa virus glycoprotein complex. Hartley guinea pigs were vaccinated with two 10 µg doses, 28 days apart, of either construct. Vaccination induced strong binding antibody responses, specific to the prefusion conformation of glycoprotein complex, which were significantly higher in the prefusion stabilized glycoprotein complex construct group and displayed strong Fc-mediated effects. However, Lassa virus-neutralizing antibody activity was detected in some but not all animals. Following the challenge with a lethal dose of the Lassa virus, all vaccinated animals were protected from death and severe disease. Although the definitive mechanism of protection is still unknown, and assessment of the cell-mediated immune response was not investigated in this study, these data demonstrate the promise of mRNA as a vaccine platform against the Lassa virus and that protection against Lassa virus can be achieved in the absence of virus-neutralizing antibodies.
Topics: Humans; Guinea Pigs; Animals; Lassa virus; Antibodies, Neutralizing; Arenaviridae; mRNA Vaccines; Glycoproteins
PubMed: 37699929
DOI: 10.1038/s41467-023-41376-6 -
Current Opinion in Virology Aug 2018The structure of a prefusion arenavirus GPC was enigmatic for many years, owing to the metastable and non-covalent nature of the association between the receptor binding... (Review)
Review
The structure of a prefusion arenavirus GPC was enigmatic for many years, owing to the metastable and non-covalent nature of the association between the receptor binding and fusion subunits. Recent engineering efforts to stabilize the glycoprotein of the Old World arenavirus Lassa in a native, yet cleaved state, allowed the first structure of any arenavirus prefusion GPC trimer to be determined. Comparison of this structure with the structures of other arenavirus glycoprotein subunits reveals surprising findings: that the receptor binding subunit, GP1, of Lassa virus is conformationally labile, while the GP1 subunit of New World arenaviruses is not, and that the arenavirus GPC adopts a trimeric state unlike other glycoproteins with similar fusion machinery. Structural analysis, combined with recent biochemical data regarding antibody epitopes and receptor binding requirements, provides a basis for rational vaccine design.
Topics: Arenavirus; Epitopes; Glycoproteins; Humans; Lassa virus; Protein Binding; Protein Structure, Tertiary; Viral Envelope Proteins; Virus Internalization
PubMed: 29843991
DOI: 10.1016/j.coviro.2018.05.002