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- Volume 2, 2015
Annual Review of Virology - Volume 2, 2015
Volume 2, 2015
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Novel Functions of the Human Papillomavirus E6 Oncoproteins
Vol. 2 (2015), pp. 403–423More LessHuman papillomaviruses (HPVs) infect the epidermis as well as mucous membranes of humans. They are the causative agents of anogenital tract and some oropharyngeal cancers. Infections begin in the basal epithelia, where the viral genome replicates slowly along with its host cell. As infected cells begin to differentiate and progress toward the periphery, the virus drives proliferation in cells that would otherwise be quiescent. To uncouple differentiation from continued cellular propagation, HPVs express two oncoproteins, HPV E6 and E7. This review focuses on high-risk α-HPV E6, which in addition to supporting viral replication has transforming properties. HPV E6 promotes p53 degradation and activates telomerase, but the multifaceted oncoprotein has numerous other functions that are highlighted here.
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Parvovirus Family Conundrum: What Makes a Killer?
Vol. 2 (2015), pp. 425–450More LessParvoviruses infect a wide variety of hosts, and their ancestors appear to have emerged tens to hundreds of millions of years ago and to have spread widely ever since. The diversity of parvoviruses is therefore extensive, and although they all appear to descend from a common ancestor and share common structures in their capsid and nonstructural proteins, there is often low homology at the DNA or protein level. The diversity of these viruses is also seen in the widely differing impacts they have on their hosts, which range from severe and even lethal disease to subclinical or nonpathogenic infections. In the past few years, deep sequencing of DNA samples from animals has shown just how widespread the parvoviruses are in nature, but most of the newly discovered viruses have not yet been associated with any disease. However, variants of some parvoviruses have altered their host ranges to create new epidemic or pandemic viruses. Here, we examine the properties of parvoviruses and their interactions with their hosts that are associated with these disparate pathogenic outcomes.
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Everything You Always Wanted to Know About Rabies Virus (But Were Afraid to Ask)
Vol. 2 (2015), pp. 451–471More LessThe cultural impact of rabies, the fatal neurological disease caused by infection with rabies virus, registers throughout recorded history. Although rabies has been the subject of large-scale public health interventions, chiefly through vaccination efforts, the disease continues to take the lives of about 40,000–70,000 people per year, roughly 40% of whom are children. Most of these deaths occur in resource-poor countries, where lack of infrastructure prevents timely reporting and postexposure prophylaxis and the ubiquity of domestic and wild animal hosts makes eradication unlikely. Moreover, although the disease is rarer than other human infections such as influenza, the prognosis following a bite from a rabid animal is poor: There is currently no effective treatment that will save the life of a symptomatic rabies patient. This review focuses on the major unanswered research questions related to rabies virus pathogenesis, especially those connecting the disease progression of rabies with the complex dysfunction caused by the virus in infected cells. The recent applications of cutting-edge research strategies to this question are described in detail.
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Pathophysiological Consequences of Calcium-Conducting Viroporins
Vol. 2 (2015), pp. 473–496More LessEukaryotic cells have evolved a myriad of ion channels, transporters, and pumps to maintain and regulate transmembrane ion gradients. As intracellular parasites, viruses also have evolved ion channel proteins, called viroporins, which disrupt normal ionic homeostasis to promote viral replication and pathogenesis. The first viral ion channel (influenza M2 protein) was confirmed only 23 years ago, and since then studies on M2 and many other viroporins have shown they serve critical functions in virus entry, replication, morphogenesis, and immune evasion. As new candidate viroporins and viroporin-mediated functions are being discovered, we review the experimental criteria for viroporin identification and characterization to facilitate consistency within this field of research. Then we review recent studies on how the few Ca2+-conducting viroporins exploit host signaling pathways, including store-operated Ca2+ entry, autophagy, and inflammasome activation. These viroporin-induced aberrant Ca2+ signals cause pathophysiological changes resulting in diarrhea, vomiting, and proinflammatory diseases, making both the viroporin and host Ca2+ signaling pathways potential therapeutic targets for antiviral drugs.
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Virus-Host Interactions: From Unbiased Genetic Screens to Function
Holly Ramage, and Sara CherryVol. 2 (2015), pp. 497–524More LessDeciphering the many interactions that occur between a virus and host cell over the course of infection is paramount to understanding mechanisms of pathogenesis and to the future development of antiviral therapies. Over the past decade, researchers have started to understand these complicated relationships through the development of methodologies, including advances in RNA interference, proteomics, and the development of genetic tools such as haploid cell lines, allowing high-throughput screening to identify critical contact points between virus and host. These advances have produced a wealth of data regarding host factors hijacked by viruses to promote infection, as well as antiviral factors responsible for subverting viral infection. This review highlights findings from virus-host screens and discusses our thoughts on the direction of screening strategies moving forward.
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Viruses in Rodent Colonies: Lessons Learned from Murine Noroviruses
Vol. 2 (2015), pp. 525–548More LessNoroviruses (NoVs) are highly prevalent, positive-sense RNA viruses that infect a range of mammals, including humans and mice. Murine noroviruses (MuNoVs) are the most prevalent pathogens in biomedical research colonies, and they have been used extensively as a model system for human noroviruses (HuNoVs). Despite recent successes in culturing HuNoVs in the laboratory and a small animal host, studies of human viruses have inherent limitations. Thus, owing to its versatility, the MuNoV system—with its native host, reverse genetics, and cell culture systems—will continue to provide important insights into NoV and enteric virus biology. In the current review, we summarize recent findings from MuNoVs that increase our understanding of enteric virus pathogenesis and highlight similarities between human and murine NoVs that underscore the value of MuNoVs to inform studies of HuNoV biology. We also discuss the potential of endemic MuNoV infections to impact other disease models.
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No Love Lost Between Viruses and Interferons
Vol. 2 (2015), pp. 549–572More LessThe interferon system protects mammals against virus infections. There are several types of interferons, which are characterized by their ability to inhibit virus replication and resultant pathogenesis by triggering both innate and cell-mediated immune responses. Virus infection is sensed by a variety of cellular pattern-recognition receptors and triggers the synthesis of interferons, which are secreted by the infected cells. In uninfected cells, cell surface receptors recognize the secreted interferons and activate intracellular signaling pathways that induce the expression of interferon-stimulated genes; the proteins encoded by these genes inhibit different stages of virus replication. To avoid extinction, almost all viruses have evolved mechanisms to defend themselves against the interferon system. Consequently, a dynamic equilibrium of survival is established between the virus and its host, an equilibrium that can be shifted to the host's favor by the use of exogenous interferon as a therapeutic antiviral agent.
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Innate and Adaptive Immune Regulation During Chronic Viral Infections
Vol. 2 (2015), pp. 573–597More LessChronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8+ T cell functions, and specialization of CD4+ T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications.
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Bacteriophage Therapy: Advances in Formulation Strategies and Human Clinical Trials
Vol. 2 (2015), pp. 599–618More LessRecently, a number of phage therapy phase I and II safety trials have been concluded, showing no notable safety concerns associated with the use of phage. Though hurdles for efficient treatment remain, these trials hold promise for future phase III clinical trials. Interestingly, most phage formulations used in these clinical trials are straightforward phage suspensions, and not much research has focused on the processing of phage cocktails in specific pharmaceutical dosage forms. Additional research on formulation strategies and the stability of phage-based drugs will be of key importance, especially with phage therapy advancing toward phase III clinical trials.
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