Current opinion in virology最新文献

Under constant barrage by viruses, hosts have evolved a plethora of antiviral effectors and defense mechanisms. To survive, viruses must adapt to evade or subvert these defenses while still capturing cellular resources to fuel their replication cycles. Large-scale studies of the antiviral activities of cellular proteins and processes have shown that different viruses are controlled by distinct subsets of antiviral genes. The remaining antiviral genes are either ineffective in controlling infection, or in some cases, actually promote infection. In these cases, classically defined antiviral factors are retasked by viruses to enhance viral replication. This creates a more nuanced picture revealing the contextual nature of antiviral activity. The same protein can exert different effects on replication, depending on multiple factors, including the host, the target cells, and the specific virus infecting it. Here, we review numerous examples of viruses hijacking canonically antiviral proteins and retasking them for proviral purposes.

Poxviruses are large double-stranded DNA viruses that encode their own DNA replication, transcription, and mRNA biogenesis machinery, which underlies their ability to replicate entirely in the cytoplasm. However, like all other viruses, poxviruses remain dependent on host ribosomes to translate their mRNAs into the viral proteins needed to complete their replication cycle. While earlier studies established a fundamental understanding of how poxviruses wrestle with their hosts for control of translation initiation and elongation factors that guide ribosome recruitment and mRNA decoding, recent work has begun to reveal the extent to which poxviruses directly target the ribosome itself. This review summarizes our current understanding of the regulation of ribosomes and translation in poxvirus infection.

Control of gene expression, including transcription, is central in dictating the outcome of viral infection. One of the profound alterations induced by viruses is modification to the integrity and function of eukaryotic RNA polymerase II (Pol II). Here, we discuss how infection perturbs the Pol II complex by altering subunit phosphorylation and turnover, as well as how cellular genotoxic stress (e.g. DNA damage) elicits similar outcomes. By highlighting emerging parallels and differences in Pol II control during viral infection and abiotic stress, we hope to bolster identification of pathways that target Pol II and regulate the transcriptome.

Herpesviruses, such as Epstein–Barr virus (EBV), encode multiple viral microRNAs that are expressed throughout various infection stages. While much progress has been made in evaluating both the viral and host microRNAs (miRNAs) that are detected during infection as well as elucidating their molecular targets in vitro, our understanding of their contributions to pathogenesis in vivo, viral oncogenesis, and clinical implications for these small molecules remains limited. miRNAs are widely recognized as key regulators of global cellular processes, including apoptosis, cell differentiation, and development of immune responses. This review discusses the roles of miRNAs in EBV infection and current advances in miRNA-based diagnostic and therapeutic strategies potentially applicable toward EBV-associated diseases.

The intimate relationship between virus and host cell can result in highly adapted viruses that are restricted to a single host. However, some viruses have the ability to infect multiple host species. Remarkably, hepatitis E viruses (HEV) comprise genotypes that are either ‘single-host’ or ‘multi-host’ genotypes, a trait that raises fundamental questions: Why do different genotypes differ in their host range, despite a high degree of genomic similarity? What are the underlying molecular determinants that shape species barriers? Here, we review the current knowledge of viral and host determinants that may affect the evolutionary trajectories of HEV. We also provide a perspective on techniques and methods that address open questions of HEV host range and adaptation.

Positive-strand RNA viruses replicate in intracellular membranous structures formed after virus-driven intensive manipulation of subcellular organelles and membranes. These unique structures are called viral-replication organelles (VROs). To build VROs, the replication proteins coded by (+)RNA viruses co-opt host proteins, including membrane-shaping, lipid synthesis, and lipid-modification enzymes to create an optimal microenvironment that (i) concentrates the viral replicase and associated host proteins and the viral RNAs; (ii) regulates enzymatic activities and spatiotemporally the replication process; and (iii) protects the viral RNAs from recognition and degradation by the host innate immune defense. Tomato bushy stunt virus (TBSV), a plant (+)RNA virus, serves as an advanced model to study the interplay among viral components, co-opted host proteins, lipids, and membranes. This review presents our current understanding of the complex interaction between TBSV and host with panviral implications.

Hepatitis C virus (HCV) is unable to infect mice, a fact that has severely limited their use as small-animal models for HCV pathogenesis and as tools for HCV vaccine development. HCV is blocked at various stages of its life cycle in mouse cells, due to incompatibility with host factors, the presence of dominant restriction factors, and effective immune responses. Molecular mechanisms for several such blocks have been characterized. The stepwise understanding of these limitations in mice will enable the development of an immunocompetent mouse that can fully support HCV infection and exhibit disease similar to that of infected humans.

Epstein–Barr virus (EBV) establishes a lifelong latent infection that can be a causal agent for a diverse spectrum of cancers and autoimmune disease. A complex and dynamic viral lifecycle evades eradication by the host immune system and confounds antiviral therapeutic strategies. To date, there are no clinically approved vaccines or therapies that selectively target EBV as the underlying cause of EBV-associated disease. Here, we review the challenges and recent advances in the development of EBV-specific therapeutics for treatment of EBV-associated cancers.

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). Here, we review what is known about human gene essentiality in PEL-derived cell lines. We provide an updated list of PEL-specific human gene dependencies, based on the improved definition of core essential genes across human cancer types. The requirements of PEL cell lines for interferon regulatory factor 4 (IRF4), basic leukine zipper ATF-like transcription factor (BATF), G1/S cyclin D2 (CCND2), CASP8 and FADD like apoptosis regulator (CFLAR), MCL1 apoptosis regulator (MCL1), and murine double minute 2 (MDM2) have been confirmed experimentally. KSHV co-opts IRF4 and BATF to drive superenhancer (SE)-mediated expression of IRF4 itself, MYC, and CCND2. IRF4 dependency of SE-mediated gene expression is shared with Epstein–Barr virus-transformed lymphoblastoid cell lines (LCLs) and human T-cell leukemia virus type 1-transformed adult T-cell leukemia/lymphoma (ATLL) cell lines, as well as several B-cell lymphomas of nonviral etiology. LCLs and ATLL cell lines similarly share dependencies on CCND2 and CFLAR with PEL, but also have distinct gene dependencies. Genetic dependencies could be exploited for therapeutic intervention in PEL and other cancers.