Structural insights into the coupling of virion assembly and rotavirus replication

Rotavirus Molecular Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Reviews Microbiology (Impact Factor: 23.57). 01/2012; 10(3):165-77. DOI: 10.1038/nrmicro2673
Source: PubMed


Viral replication is rapid and robust, but it is far from a chaotic process. Instead, successful production of infectious progeny requires that events occur in the correct place and at the correct time. Rotaviruses (segmented double-stranded RNA viruses of the Reoviridae family) seem to govern their replication through ordered disassembly and assembly of a triple-layered icosahedral capsid. In recent years, high-resolution structural data have provided unprecedented insight into these events. In this Review, we explore the current understanding of rotavirus replication and how it compares to replication of other Reoviridae family members.

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    • "However, because it is not the surface viron protein, VP6 protein elicits only the immunity inhibiting intracellular replication of rotavirus in infected intestinal cells [26], but does not induce neutralizing antibodies which prevent the rotavirus infection. Rotavirus VP4 (which defines P type) and VP7 (which defines G type) are two independent neutralizing antigens, which constitute the outermost layer capsid of rotavirus [26]. Non-glycosylated VP4 forms the spikes of rotavirus that extended from the viral particle surface, while glycosylated VP7 forms the smooth shell of the virion. "
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    ABSTRACT: The cell-attachment protein VP8* of rotavirus is a potential candidate parenteral vaccine. However, the yield of full-length VP8 protein (VP8*, residues 1-231) expressed in Escherichia coli was low, and a truncated VP8 protein (ΔVP8*, residues 65-231) cannot elicit efficient protective immunity in a mouse model. In this study, tow novel truncated VP8 proteins, VP8-1 (residues 26-231) and VP8-2 (residues 51-231), were expressed in E. coli and evaluated for immunogenicity and protective efficacy, compared with VP8* and ΔVP8*. As well as ΔVP8*, the protein VP8-1 and VP8-2 were successfully expressed in high yield and purified in homogeneous dimeric forms, while the protein VP8* was expressed with lower yield and prone to aggregation and degradation in solution. Although the immunogenicity of the protein VP8*, VP8-1, VP8-2 and ΔVP8* was comparable, immunization of VP8* and VP8-1 elicited significantly higher neutralizing antibody titers than that of VP8-2 and ΔVP8* in mice. Furthermore, when assessed using a mouse maternal antibody model, the efficacy of VP8-1 to protect against rotavirus-induced diarrhea in pups was comparable to that of VP8*, both were dramatically higher than that of VP8-2 and ΔVP8*. Taken together, the novel truncated protein VP8-1, with increased yield, improved homogeneity and high protective efficacy, is a viable candidate for further development of a parenterally administrated prophylactic vaccine against rotavirus infection. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Apr 2015 · Vaccine
    • "Capping by VP3 is incompletely efficient, which results in populations of uncapped and partially capped viral transcripts that activate host innate immune responses through the RNA-sensing PRRs RIG-I and melanoma differentiation-associated protein 5 (MDA5) (Broquet et al., 2011; Sen et al., 2011; Uzri and Greenberg, 2013). Genome replication and virion assembly are coordinated within cytoplasmic inclusions, or viroplasms, that likely serve to conceal dsRNA gene segments from detection by the host PRR machinery (Patton et al., 2006; Trask et al., 2012). Newly synthesized DLPs acquire their outer VP4/VP7 layer by budding through the endoplasmic reticulum, after which progeny virions exit the cell by lysis or exocytosis (Desselberger, 2014). "
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    ABSTRACT: The innate immune response involves a broad array of pathogen sensors that stimulate the production of interferons (IFNs) to induce an antiviral state. Rotavirus, a significant cause of childhood gastroenteritis and a member of the Reoviridae family of segmented, double-stranded RNA viruses, encodes at least two direct antagonists of host innate immunity: NSP1 and VP3. NSP1, a putative E3 ubiquitin ligase, mediates the degradation of cellular factors involved in both IFN induction and downstream signaling. VP3, the viral capping enzyme, utilizes a 2H-phosphodiesterase domain to prevent activation of the cellular oligoadenylate synthase (OAS)/RNase L pathway. Computational, molecular, and biochemical studies have provided key insights into the structural and mechanistic basis of innate immune antagonism by NSP1 and VP3 of group A rotaviruses (RVA). Future studies with non-RVA isolates will be essential to understand how other rotavirus species evade host innate immune responses. Published by Elsevier Inc.
    No preview · Article · Feb 2015 · Virology
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    • "Rotavirus studies propose that the double-layered particle (DLP)–VP4–NSP4 complex breaches the ER membrane and penetrates into the ER. The viral capsid protein, VP7, re-envelopes the immature particle (DLP) after removal of the ER membrane and NSP4, and forms the infectious triple-layered particle (Tian et al., 1996; Trask et al., 2012). "
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    ABSTRACT: Endoplasmic reticulum (ER) stress is a general term for representing the pathway by which various stimuli affect ER functions. ER stress induces the evolutionarily conserved signaling pathways, called the unfolded protein response (UPR), which compromises the stimulus and then determines whether the cell survives or dies. In recent years, ongoing research has suggested that these pathways may be linked to the autophagic response, which plays a key role in the cell's response to various stressors. Autophagy performs a self-digestion function, and its activation protects cells against certain pathogens. However, the link between the UPR and autophagy may be more complicated. These two systems may act dependently, or the induction of one system may interfere with the other. Experimental studies have found that different viruses modulate these mechanisms to allow them to escape the host immune response or, worse, to exploit the host's defense to their advantage; thus, this topic is a critical area in antiviral research. In this review, we summarize the current knowledge about how RNA viruses, including influenza virus, poliovirus, coxsackievirus, enterovirus 71, Japanese encephalitis virus, hepatitis C virus, and dengue virus, regulate these processes. We also discuss recent discoveries and how these will produce novel strategies for antiviral treatment.
    Full-text · Article · Aug 2014 · Frontiers in Microbiology
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