病毒与宿主细胞的糖基化修饰及相关功能

病毒的复制和对宿主的入侵与自身结构蛋白的糖基化修饰密切相关.对于宿主而言,在病毒感染宿主和宿主抗病毒的过程中,宿主的糖基化过程一方面可抑制病毒的复制和入侵,另一方面可促进病毒对宿主的感染,抑制宿主糖苷酶可抑制病毒的复制.从病毒方面来看,由于病毒自身缺乏糖基化修饰系统,病毒的糖基化过程是借宿主细胞内的合成系统对自身进行糖基化修饰.病毒的糖基化过程对病毒蛋白的折叠与稳定、病毒的感染和入侵、参与识别宿主细胞受体和参与病毒的免疫逃逸等过程起着重要的作用.随着糖基化研究技术的发展,以糖基化为基础的功能应用也越来越深入:如新型病毒疫苗和新型抗病毒药物的研制,以糖蛋白质组学研究为基础的质谱技术和生物信息学方法的发展,以及利用糖基化对病毒性疾病的诊断和治疗等,这些均为糖基化深入研究发展奠定了基础.本文就病毒与宿主细胞糖基化过程、相关功能以及研究应用等进展作一综述.     

病毒蛋白质组学: 病毒学研究前沿

病毒寄生于宿主细胞中, 需要不断地适应和改变宿主的环境. 它们能够编码多种多功能蛋白质, 这些蛋白能与宿主蛋白发生一系列的相互作用以完成病毒的各种功能. 迄今, 尽管许多病毒的基因组已测序完成, 但由于受到病毒影响而发生相应改变的宿主蛋白组、宿主蛋白翻译后修饰, 以及蛋白酶剪接过程还未被完全阐明. 近年来新兴的高通量技术, 如基于质谱技术的定量或半定量蛋白组方法, 已被广泛应用于病毒宿主相互作用的研究中, 且有望在上述领域取得突破性进展. 本综述主要探讨蛋白质组学研究中的病毒颗粒蛋白质组学, 病毒结构蛋白质组学和病毒影响的宿主蛋白质组学等病毒蛋白质组学中的前沿领域.     

植物中病毒来源的小RNA介导的RNA沉默

植物RNA 沉默机制的主要功能之一是具有抗病毒作用. 在被病毒侵染的宿主细胞中发现的病毒来源的小RNA表明, 宿主的RNA沉默机制可以靶向病毒RNA. 随着vsiRNAs 高通量测序技术的发展, 近年来的遗传学研究揭示了vsiRNAs 的起源和组成以及它们调控基因表达的潜在功能. 本文简述了vsiRNAs 的起源和生物合成过程, 并着重围绕在抗病毒过程中vsiRNAs 介导的对病毒基因组和宿主转录本的RNA 沉默现象进行综述, 以更好地理解植物中vsiRNAs 在病毒致病性以及和宿主互作中的作用机制.     

病毒RNA如何逃避宿主细胞的降解

细胞RNA的降解机制不仅在基因表达调节方面具有重要作用,而且也是一种重要的病毒防御机制. 作为一种必须在细胞内增殖的微生物,病毒已经进化出了多种机制,以保护它们的RNA免被宿主细胞降解,如病毒RNA模拟宿主细胞mRNA的结构、形成磷脂包膜、形成局部二级结构、结合自己或宿主细胞编码的蛋白质和编码核酸酶增强宿主细胞mRNA降解等. 本文主要论述了病毒RNA逃避宿主细胞降解的方式,并对其应用前景进行了展望,尤其是在研发抗病毒药物方面的应用前景.     

囊膜病毒膜融合的分子机制

囊膜病毒可能采用相似的病毒-宿主细胞膜融合机制,即病毒表面糖蛋白结合到宿主细胞受体后,启动了病毒融合蛋白的一系列构象变化,根据囊膜蛋白构象变化特征,囊膜病毒可采用两种以上的方式发生膜融合,并据此分为两类：Ⅰ型病毒膜融合和Ⅱ型病毒膜融合.Ⅱ型病毒膜融合以黄病毒为代表,其分子机制与Ⅰ型病毒膜融合不同,但不很清楚.而Ⅰ型病毒膜融合中,如艾滋病毒,流感病毒等,在囊膜蛋白变构形成稳定折叠的发夹三聚体结构时,拉近了两膜之间的距离,此过程释放出来的能量进一步促使两膜融合.膜融合使病毒蛋白及病毒RNA基因组释放到宿主细胞内而感染宿主.以上述研究为基础设计的C肽/N肽小分子抑制子, 可以在病毒糖蛋白中间体构象形成的短时间内,高效、特异地竞争结合其配体,从而阻止糖蛋白的进一步折叠,达到抑制病毒入侵的目的,为病毒疾病的防治提供了新思路和策略.针对艾滋病毒设计的C肽,即T20或Enfuvirtide在临床应用效果很好.以艾滋病毒和流感病毒为例,主要对Ⅰ型病毒膜融合的研究进展进行了讨论.     

综述: 病毒与宿主细胞的糖基化修饰及相关功能

病毒的复制和对宿主的入侵与自身结构蛋白的糖基化修饰密切相关．对于宿主而言,在病毒感染宿主和宿主抗病毒的过程中,宿主的糖基化过程一方面可抑制病毒的复制和入侵,另一方面可促进病毒对宿主的感染,抑制宿主糖苷酶可抑制病毒的复制．从病毒方面来看,由于病毒自身缺乏糖基化修饰系统,病毒的糖基化过程是借宿主细胞内的合成系统对自身进行糖基化修饰．病毒的糖基化过程对病毒蛋白的折叠与稳定、病毒的感染和入侵、参与识别宿主细胞受体和参与病毒的免疫逃逸等过程起着重要的作用．随着糖基化研究技术的发展,以糖基化为基础的功能应用也越来越深入：如新型病毒疫苗和新型抗病毒药物的研制,以糖蛋白质组学研究为基础的质谱技术和生物信息学方法的发展,以及利用糖基化对病毒性疾病的诊断和治疗等,这些均为糖基化深入研究发展奠定了基础．本文就病毒与宿主细胞糖基化过程、相关功能以及研究应用等进展作一综述．     

病毒感染蛋白质组学研究进展

病毒的侵入会导致宿主细胞蛋白表达模式的改变,这种改变将影响宿主细胞的正常生理功能并决定病毒的致病进程和结果.因此,病毒感染蛋白质组学研究有助于揭示病毒与宿主的相互作用机制和病毒的分子致病机制,以及寻找病毒早期感染的分子标记、建立早期诊断方法、评价治疗效果和预后.本文介绍了病毒感染蛋白质组学研究技术、病毒诱导宿主细胞蛋白质组改变和病毒感染宿主血清差异蛋白质组等方面的研究进展.     

microRNA与病毒感染

microRNA是一类新近发现的由20-23个核苷酸构成的非编码RNA分子,它在生命进程中起着重要作用.病毒的复制和繁殖依赖于宿主细胞,而且对细胞环境的变化敏感.研究表明宿主和病毒都可以编码microRNA,病毒可通过小RNA介导的干扰作用影响宿主细胞,也能利用自身的"独特战略"改变宿主细胞从而满足自己生存的需求,所以,宿主与病毒间存在microRNA-mRNA相互作用的机制.尽管时microRNA与病毒感染的关系研究时间不长,但目前的研究结果为我们理解病毒和宿主之间的相互作用提供了一条途径,并为寻找病毒感染的生物标志物和治疗方法提供了新的思路.     

宿主细胞膜骨架蛋白在病毒感染复制中作用的研究进展

病毒与宿主细胞之间相互关系的研究不仅具有重要的理论意义,也是重大的医学实践课题.病毒可以与宿主蛋白相互作用并改变细胞的正常功能,从而促进病毒的感染与复制.宿主细胞膜骨架蛋白在病毒的生命周期中起着重要作用,研究表明细胞膜骨架蛋白参与了病毒的感染及复制,尽管许多精细机制尚不清楚,但这扩展了人们对细胞膜骨架蛋白功能的理解.本文重点介绍宿主细胞膜骨架蛋白如肌动蛋白、血影蛋白在病毒进入、细胞内运输、组装和释放等病毒感染复制过程中的作用.     

病毒-宿主蛋白相互作用组学研究进展

病毒和宿主之间的蛋白相互作用贯穿其整个生命周期.对病毒-宿主蛋白相互作用组的研究不仅可以阐明病毒的感染过程和机体的防御机制,而且还可以揭示潜在的抗病毒治疗靶点.本文回顾了病毒-宿主蛋白相互作用组学常用的研究方法,并探讨了每种方法的优点及局限性.     

A systems biology approach to the evolution of plant-virus interactions

Omic approaches to the analysis of plant-virus interactions are becoming increasingly popular. These types of data, in combination with models of interaction networks, will aid in revealing not only host components that are important for the virus life cycle, but also general patterns about the way in which different viruses manipulate host regulation of gene expression for their own benefit and possible mechanisms by which viruses evade host defenses. Here, we review studies identifying host genes regulated by viruses and discuss how these genes integrate in host regulatory and interaction networks, with a particular focus on the physical properties of these networks.     

Codon usage signatures in Sabia and Chapare for host adaptation

Sabia and Chapare viruses in the Arenavirus family cause viral hemorrhagic fever among humans with a fatality rate of 30% with no treatment models. Therefore, it is of interest to document the codon usage, amino acid patterns and associated factors influencing the observed variations in Sabia and Chapare viruses for host adaptation. Multivariate statistical analysis revealed compositional constraint and host selection pressure influencing the viral codon usage patterns. These data suggests the codon usage signatures in Sabia and Chapare viruses for host adaptation in the human host implying its role in the rapid progression of the infection. Dinucleotides UpG and CpA were noted to be over-represented among the Sabia, Chapare viruses and human genomes. Strong restraint from the usage of CpG dinucleotides among viruses is linked with the molecular mimicry of the human immune system. Thus, the data reported from this study help in understanding the mechanism of viral adaptation inside the host genome for further consideration in drug discovery.     

Utility of DNA viruses for studying human host history: case study of JC virus

Microbial pathogens, and viruses in particular, can serve as important complements to traditional genetic markers when investigating the population histories of their human host. The range of mutation rates for DNA viruses suggests that DNA viruses can be useful markers of both recent and ancient events in their host histories. Here, we assess the utility of a well known DNA virus, JC virus (JCV), for investigating human history and demography. Using complete coding viral genomes, we confirm the phylogeographic structure of JCV in populations worldwide and provide coalescent estimates of its evolutionary rate under two alternative models of its history. Using these rate estimates, we compare Bayesian skyline plots of population size changes for JCV to those of its human host as estimated with coding mitochondrial genomes of the latter. These comparisons, when combined with other evidence including a log Bayes Factor model test, show that JCV is evolving rapidly and is therefore tracking the recent history of its human host. These results support the hypothesis that post-World War II societal changes are most likely responsible for the recent demographic patterns observed among different regional JCV populations. In sum, fast evolving DNA viruses, such as JCV, can complement RNA viruses to provide novel insights about the recent history and demography of their human host.     

A SIMPLE MODEL EXPLAINS THE DYNAMICS OF PREFERENTIAL HOST SWITCHING AMONG MAMMAL RNA VIRUSES

A growing number of studies support a tendency toward preferential host switching, by parasites and pathogens, over relatively short phylogenetic distances. This suggests that a host switch is more probable if a potential host is closely related to the original host than if it is a more distant relative. However, despite its importance for the health of humans, livestock, and wildlife, the detailed dynamics of preferential host switching have, so far, been little studied. We present an empirical test of two theoretical models of preferential host switching, using observed phylogenetic distributions of host species for RNA viruses of three mammal orders (primates, carnivores, and ungulates). The analysis focuses on multihost RNA virus species, because their presence on multiple hosts and their estimated ages of origin indicate recent host switching. Approximate Bayesian computation was used to compare observed phylogenetic distances between hosts with those simulated under the theoretical models. The results support a decreasing sigmoidal model of preferential host switching, with a strong effect from increasing phylogenetic distance, on all three studied host phylogenies. This suggests that the dynamics of host switching are fundamentally similar for RNA viruses of different mammal orders and, potentially, a wider range of coevolutionary systems.     

The variable codons of H5N1 avian influenza A virus haemagglutinin genes

We investigated the selection pressures on the haemagglutinin genes of H5N1 avian influenza viruses using fixed effects likelihood models. We found evidence of positive selection in the sequences from isolates from 1997 to 2007, except viruses from 2000. The haemagglutinin sequences of viruses from southeast Asia, Hong Kong and mainland China were the most polymorphic and had similar nonsynonymous profiles. Some sites were positively selected in viruses from most regions and a few of these sites displayed different amino acid patterns. Selection appeared to produce different outcomes in viruses from Europe, Africa and Russia and from different host types. One position was found to be positively selected for human isolates only. Although the functions of some positively selected positions are unknown, our analysis provided evidence of different temporal, spatial and host adaptations for H5N1 avian influenza viruses.     

Viral proteins acquired from a host converge to simplified domain architectures

The infection cycle of viruses creates many opportunities for the exchange of genetic material with the host. Many viruses integrate their sequences into the genome of their host for replication. These processes may lead to the virus acquisition of host sequences. Such sequences are prone to accumulation of mutations and deletions. However, in rare instances, sequences acquired from a host become beneficial for the virus. We searched for unexpected sequence similarity among the 900,000 viral proteins and all proteins from cellular organisms. Here, we focus on viruses that infect metazoa. The high-conservation analysis yielded 187 instances of highly similar viral-host sequences. Only a small number of them represent viruses that hijacked host sequences. The low-conservation sequence analysis utilizes the Pfam family collection. About 5% of the 12,000 statistical models archived in Pfam are composed of viral-metazoan proteins. In about half of Pfam families, we provide indirect support for the directionality from the host to the virus. The other families are either wrongly annotated or reflect an extensive sequence exchange between the viruses and their hosts. In about 75% of cross-taxa Pfam families, the viral proteins are significantly shorter than their metazoan counterparts. The tendency for shorter viral proteins relative to their related host proteins accounts for the acquisition of only a fragment of the host gene, the elimination of an internal domain and shortening of the linkers between domains. We conclude that, along viral evolution, the host-originated sequences accommodate simplified domain compositions. We postulate that the trimmed proteins act by interfering with the fundamental function of the host including intracellular signaling, post-translational modification, protein-protein interaction networks and cellular trafficking. We compiled a collection of hijacked protein sequences. These sequences are attractive targets for manipulation of viral infection.     

Identifying and prioritizing potential human-infecting viruses from their genome sequences

Determining which animal viruses may be capable of infecting humans is currently intractable at the time of their discovery, precluding prioritization of high-risk viruses for early investigation and outbreak preparedness. Given the increasing use of genomics in virus discovery and the otherwise sparse knowledge of the biology of newly discovered viruses, we developed machine learning models that identify candidate zoonoses solely using signatures of host range encoded in viral genomes. Within a dataset of 861 viral species with known zoonotic status, our approach outperformed models based on the phylogenetic relatedness of viruses to known human-infecting viruses (area under the receiver operating characteristic curve [AUC] = 0.773), distinguishing high-risk viruses within families that contain a minority of human-infecting species and identifying putatively undetected or so far unrealized zoonoses. Analyses of the underpinnings of model predictions suggested the existence of generalizable features of viral genomes that are independent of virus taxonomic relationships and that may preadapt viruses to infect humans. Our model reduced a second set of 645 animal-associated viruses that were excluded from training to 272 high and 41 very high-risk candidate zoonoses and showed significantly elevated predicted zoonotic risk in viruses from nonhuman primates, but not other mammalian or avian host groups. A second application showed that our models could have identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) as a relatively high-risk coronavirus strain and that this prediction required no prior knowledge of zoonotic Severe Acute Respiratory Syndrome (SARS)-related coronaviruses. Genome-based zoonotic risk assessment provides a rapid, low-cost approach to enable evidence-driven virus surveillance and increases the feasibility of downstream biological and ecological characterization of viruses.

Surveillance of emerging viruses is one of the first steps to avoid the next pandemic. This study uses machine learning to identify many zoonotic viruses directly from their genomes. This allows rapid assessment of research priorities as soon as new viruses are discovered, focusing research and surveillance efforts on the viruses most likely to infect humans.     

The variable codons of H5N1 avian influenza A virus haemagglutinin genes

We investigated the selection pressures on the haemagglutinin genes of H5N1 avian influenza viruses using fixed effects likelihood models. We found evidence of positive selection in the sequences from isolates from 1997 to 2007, except viruses from 2000. The haemagglutinin sequences of viruses from southeast Asia, Hong Kong and mainland China were the most polymorphic and had similar nonsyn-onymous profiles. Some sites were positively selected in viruses from most regions and a few of these sites displayed different amino acid patterns. Selection appeared to produce different outcomes in vi-ruses from Europe, Africa and Russia and from different host types. One position was found to be positively selected for human isolates only. Although the functions of some positively selected posi-tions are unknown, our analysis provided evidence of different temporal, spatial and host adaptations for H5N1 avian influenza viruses.     

Dynamics of cytotoxic T-lymphocyte exhaustion.

We examine simple mathematical models to investigate the circumstances under which the dynamics of cytotoxic T-lymphocyte (CTL) activation and differentiation may result in the loss of virus specific CD8+ cells, a process known as CTL exhaustion. We distinguish between two general classes of viruses: (i) viruses infecting cells that are not involved in the immune response; and (ii) viruses infecting antigen presenting cells (APCs) and helper cells. The models specify host and viral properties that lead to CTL exhaustion and indicate that this phenomenon is only likely to be observed with viruses infecting APCs and helper cells. Moreover, it is found that for such viruses, a high rate of replication and a low degree of cytopathogenicity promote the exhaustion of the CTL response. In addition, a high initial virus load and a low CD4+ cell count promote the occurrence of CTL exhaustion. These conclusions are discussed with reference to empirical data on lymphocytic choriomeningitis virus and on human immunodeficiency virus.