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Chapter 19 : Arenaviruses
Category: Viruses and Viral Pathogenesis; Microbial Genetics and Molecular Biology
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The elucidation of the mechanisms underlying the interactions between arenaviruses and the host innate immune response is essential for a better understanding of arenavirus pathogenesis and development of antiviral therapies to combat human arenaviral diseases. The significance of arenaviruses in human health together with the very limited existing armamentarium to combat the infections underscore the importance of developing novel effective antiarenavirus therapies and vaccines, tasks that will be helped by a better understanding of the mechanisms by which arenaviruses counteract the early host innate immune response. Many arenaviruses appear to use an alternative receptor. The mechanisms by which arenaviruses disrupt the host innate immune response are little understood. The family Arenaviridae consists of one unique genus (Arenavirus) with more than 20 recognized virus species that are classified into two distinct groups: Old World and New World arenaviruses. Genetically, Old World arenaviruses constitute a single lineage, while New World arenaviruses segregate into clades A, B, and C. The viral genetic determinants contributing to pathogenesis in humans associated with some arenaviral infections remain largely unknown, but evidence suggests that virus-induced impairment of the host innate immune response is a contributing factor. The fact that nucleoprotein (NP) is the gene product with the highest degree of conservation among arenaviruses raised the question of whether the interferon (IFN)-antagonistic activity of the lymphocytic choriomeningitis virus (LCMV) NP was shared by other arenaviruses, including those involved in human disease.
Scheme of the LCMV genome organization. LCMV has a bisegmented, negative-strand RNA genome. Each segment uses an ambisense strategy to direct the synthesis of two viral gene products. The S (small, ca. 3.5 kb) segment codes for the viral nucleoprotein (NP) and precursor surface viral glycoprotein (GPC), which is posttranslationally cleaved by the cellular protease S1P to generate GP1 and GP2. GP1/GP2 complexes form the spikes that decorate the surface of the virions. The L (large, ca. 7.5 kb) segment codes for the viral RdRp (L protein) and a small (ca. 12 kDa) RING finger protein called Z.
Basic aspects of Arenavirus RNA replication and gene transcription illustrated for the S segment. Once the virus RNP is delivered into the cytoplasm of the infected cell, the polymerase associated with the virus RNP initiates transcription from the genome promoter located at the genome 3′ end. Primary transcription results in synthesis of NP and L mRNA from the S and L segments, respectively. Subsequently, the virus polymerase can adopt a replicase mode and moves across the IGR to generate a copy of the full-length antigenome RNA (agRNA). This agRNA will serve as a template for the synthesis of the GP (agS) and Z (agL) mRNAs. The agRNA species also serve as templates for the amplification of the corresponding genome RNA species.