Annual Review of Virology最新文献

Two decades of metagenomic analyses have revealed that in many environments, small (∼5 kb), single-stranded DNA phages of the family Microviridae dominate the virome. Although the emblematic microvirus phiX174 is ubiquitous in the laboratory, most other microviruses, particularly those of the gokushovirus and amoyvirus lineages, have proven to be much more elusive. This puzzling lack of representative isolates has hindered insights into microviral biology. Furthermore, the idiosyncratic size and nature of their genomes have resulted in considerable misjudgments of their actual abundance in nature. Fortunately, recent successes in microvirus isolation and improved metagenomic methodologies can now provide us with more accurate appraisals of their abundance, their hosts, and their interactions. The emerging picture is that phiX174 and its relatives are rather rare and atypical microviruses, and that a tremendous diversity of other microviruses is ready for exploration.

Protein synthesis by the ribosome is the final stage of biological information transfer and represents an irreversible commitment to gene expression. Accurate translation of messenger RNA is therefore essential to all life, and spontaneous errors by the translational machinery are highly infrequent (∼1/100,000 codons). Programmed -1 ribosomal frameshifting (-1PRF) is a mechanism in which the elongating ribosome is induced at high frequency to slip backward by one nucleotide at a defined position and to continue translation in the new reading frame. This is exploited as a translational regulation strategy by hundreds of RNA viruses, which rely on -1PRF during genome translation to control the stoichiometry of viral proteins. While early investigations of -1PRF focused on virological and biochemical aspects, the application of X-ray crystallography and cryo-electron microscopy (cryo-EM), and the advent of deep sequencing and single-molecule approaches have revealed unexpected structural diversity and mechanistic complexity. Molecular players from several model systems have now been characterized in detail, both in isolation and, more recently, in the context of the elongating ribosome. Here we provide a summary of recent advances and discuss to what extent a general model for -1PRF remains a useful way of thinking.

Negative-stranded RNA viruses are a large group of viruses that encode their genomes in RNA across multiple segments in an orientation antisense to messenger RNA. Their members infect broad ranges of hosts, and there are a number of notable human pathogens. Here, we examine the development of reverse genetic systems as applied to these virus families, emphasizing conserved approaches illustrated by some of the prominent members that cause significant human disease. We also describe the utility of their genetic systems in the development of reporter strains of the viruses and some biological insights made possible by their use. To conclude the review, we highlight some possible future uses of reporter viruses that not only will increase our basic understanding of how these viruses replicate and cause disease but also could inform the development of new approaches to therapeutically intervene.

Nuclear egress of herpesvirus capsids across the intact nuclear envelope is an exceptional vesicle-mediated nucleocytoplasmic translocation resulting in the delivery of herpesvirus capsids into the cytosol. Budding of the (nucleo)capsid at and scission from the inner nuclear membrane (INM) is mediated by the viral nuclear egress complex (NEC) resulting in a transiently enveloped virus particle in the perinuclear space followed by fusion of the primary envelope with the outer nuclear membrane (ONM). The dimeric NEC oligomerizes into a honeycomb-shaped coat underlining the INM to induce membrane curvature and scission. Mutational analyses complemented structural data defining functionally important regions. Questions remain, including where and when the NEC is formed and how membrane curvature is mediated, vesicle formation is regulated, and directionality is secured. The composition of the primary enveloped virion and the machinery mediating fusion of the primary envelope with the ONM is still debated. While NEC-mediated budding apparently follows a highly conserved mechanism, species and/or cell type-specific differences complicate understanding of later steps.

The nonsegmented, negative-strand RNA viruses (nsNSVs), also known as the order Mononegavirales, have a genome consisting of a single strand of negative-sense RNA. Integral to the nsNSV replication cycle is the viral polymerase, which is responsible for transcribing the viral genome, to produce an array of capped and polyadenylated messenger RNAs, and replicating it to produce new genomes. To perform the different steps that are necessary for these processes, the nsNSV polymerases undergo a series of coordinated conformational transitions. While much is still to be learned regarding the intersection of nsNSV polymerase dynamics, structure, and function, recently published polymerase structures, combined with a history of biochemical and molecular biology studies, have provided new insights into how nsNSV polymerases function as dynamic machines. In this review, we consider each of the steps involved in nsNSV transcription and replication and suggest how these relate to solved polymerase structures.

N- and O-glycans are both important constituents of viral envelope glycoproteins. O-linked glycosylation can be initiated by any of 20 different human polypeptide O-acetylgalactosaminyl transferases, resulting in an important functional O-glycan heterogeneity. O-glycans are organized as solitary glycans or in clusters of multiple glycans forming mucin-like domains. They are functional both in the viral life cycle and in viral colonization of their host. Negatively charged O-glycans are crucial for the interactions between glycosaminoglycan-binding viruses and their host. A novel mechanism, based on controlled electrostatic repulsion, explains how such viruses solve the conflict between optimized viral attachment to target cells and efficient egress of progeny virus. Conserved solitary O-glycans appear important for viral uptake in target cells by contributing to viral envelope fusion. Dual roles of viral O-glycans in the host B cell immune response, either epitope blocking or epitope promoting, may be exploitable for vaccine development. Finally, specific virus-induced O-glycans may be involved in viremic spread.

Host defense against viral pathogens is an essential function for all living organisms. In cell-intrinsic innate immunity, dedicated sensor proteins recognize molecular signatures of infection and communicate to downstream adaptor or effector proteins to activate immune defense. Remarkably, recent evidence demonstrates that much of the core machinery of innate immunity is shared across eukaryotic and prokaryotic domains of life. Here, we review a pioneering example of evolutionary conservation in innate immunity: the animal cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) signaling pathway and its ancestor in bacteria, CBASS (cyclic nucleotide-based antiphage signaling system) antiphage defense. We discuss the unique mechanism by which animal cGLRs (cGAS-like receptors) and bacterial CD-NTases (cGAS/dinucleotide-cyclase in Vibrio (DncV)-like nucleotidyltransferases) in these pathways link pathogen detection with immune activation using nucleotide second messenger signals. Comparing the biochemical, structural, and mechanistic details of cGAS-STING, cGLR signaling, and CBASS, we highlight emerging questions in the field and examine evolutionary pressures that may have shaped the origins of nucleotide second messenger signaling in antiviral defense.

The 1918 Spanish influenza pandemic was one of the deadliest infectious disease events in recorded history, resulting in approximately 50-100 million deaths worldwide. The origins of the 1918 virus and the molecular basis for its exceptional virulence remained a mystery for much of the 20th century because the pandemic predated virologic techniques to isolate, passage, and store influenza viruses. In the late 1990s, overlapping fragments of influenza viral RNA preserved in the tissues of several 1918 victims were amplified and sequenced. The use of influenza reverse genetics then permitted scientists to reconstruct the 1918 virus entirely from cloned complementary DNA, leading to new insights into the origin of the virus and its pathogenicity. Here, we discuss some of the advances made by resurrection of the 1918 virus, including the rise of innovative molecular research, which is a topic in the dual use debate.

Phase separation of viral biopolymers is a key factor in the formation of cytoplasmic viral inclusions, known as sites of virus replication and assembly. This review describes the mechanisms and factors that affect phase separation in viral replication and identifies potential areas for future research. Drawing inspiration from studies on cellular RNA-rich condensates, we compare the hierarchical coassembly of ribosomal RNAs and proteins in the nucleolus to the coordinated coassembly of viral RNAs and proteins taking place within viral factories in viruses containing segmented RNA genomes. We highlight the common characteristics of biomolecular condensates in viral replication and how this new understanding is reshaping our views of virus assembly mechanisms. Such studies have the potential to uncover unexplored antiviral strategies targeting these phase-separated states.

Enteric viruses display intricate adaptations to the host mucosal immune system to successfully reproduce in the gastrointestinal tract and cause maladies ranging from gastroenteritis to life-threatening disease upon extraintestinal dissemination. However, many viral infections are asymptomatic, and their presence in the gut is associated with an altered immune landscape that can be beneficial or adverse in certain contexts. Genetic variation in the host and environmental factors including the bacterial microbiota influence how the immune system responds to infections in a remarkably viral strain-specific manner. This immune response, in turn, determines whether a given virus establishes acute versus chronic infection, which may have long-lasting consequences such as susceptibility to inflammatory disease. In this review, we summarize our current understanding of the mechanisms involved in the interaction between enteric viruses and the immune system that underlie the impact of these ubiquitous infectious agents on our health.