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Special Issue "Viral Replication Complexes: Structures, Functions, Applications and Inhibitors"

A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (30 April 2015)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Guest Editor
Dr. David D. Boehr

Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Website | E-Mail
Phone: +1-814-863-8605
Fax: +1-814-863-0618
Interests: enzymes; protein biophysics; allostery; protein engineering; NMR; microbiology

Special Issue Information

Dear Colleagues,

Viruses are obligate intracellular parasites that need to co-opt a living cell’s machinery for replication. At the heart of the viral replication machinery are the nucleic acid polymerases, which are responsible for efficiently copying the viral genome. This process must often be coordinated with other viral processes including protein translation and viral packaging. The nucleic acid polymerases may also be responsible for generating genetic diversity that is important for escape from the host’s defenses. The polymerases and other components of the replication machinery may serve as potential anti-viral targets. In this Special Issue, we seek to highlight recent advances into uncovering the structure and function of viral replication complexes. We are especially seeking to highlight the wide-range of methodologies used to gain structural insight into viral replication. Topics of interest include molecular mechanisms of nucleic acid polymerases, nucleic acid recognition and translocation, fidelity and error correction, interactions with lipid membranes, and coordination/regulation of transcription, translation and replication processes.

Dr. David Boehr
Guest Editor

Manuscript Submission Information

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Keywords

  • virus
  • replication
  • polymerase
  • fidelity
  • quasi-species
  • assembly
  • nucleic acid
  • translation
  • structural biology

Published Papers (18 papers)

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Research

Jump to: Review

Open AccessArticle Conformational Ensemble of the Poliovirus 3CD Precursor Observed by MD Simulations and Confirmed by SAXS: A Strategy to Expand the Viral Proteome?
Viruses 2015, 7(11), 5962-5986; doi:10.3390/v7112919
Received: 1 June 2015 / Revised: 30 October 2015 / Accepted: 11 November 2015 / Published: 23 November 2015
Cited by 3 | PDF Full-text (6258 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
The genomes of RNA viruses are relatively small. To overcome the small-size limitation, RNA viruses assign distinct functions to the processed viral proteins and their precursors. This is exemplified by poliovirus 3CD protein. 3C protein is a protease and RNA-binding protein. 3D protein
[...] Read more.
The genomes of RNA viruses are relatively small. To overcome the small-size limitation, RNA viruses assign distinct functions to the processed viral proteins and their precursors. This is exemplified by poliovirus 3CD protein. 3C protein is a protease and RNA-binding protein. 3D protein is an RNA-dependent RNA polymerase (RdRp). 3CD exhibits unique protease and RNA-binding activities relative to 3C and is devoid of RdRp activity. The origin of these differences is unclear, since crystal structure of 3CD revealed “beads-on-a-string” structure with no significant structural differences compared to the fully processed proteins. We performed molecular dynamics (MD) simulations on 3CD to investigate its conformational dynamics. A compact conformation of 3CD was observed that was substantially different from that shown crystallographically. This new conformation explained the unique properties of 3CD relative to the individual proteins. Interestingly, simulations of mutant 3CD showed altered interface. Additionally, accelerated MD simulations uncovered a conformational ensemble of 3CD. When we elucidated the 3CD conformations in solution using small-angle X-ray scattering (SAXS) experiments a range of conformations from extended to compact was revealed, validating the MD simulations. The existence of conformational ensemble of 3CD could be viewed as a way to expand the poliovirus proteome, an observation that may extend to other viruses. Full article
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Open AccessArticle Nucleobase but not Sugar Fidelity is Maintained in the Sabin I RNA-Dependent RNA Polymerase
Viruses 2015, 7(10), 5571-5586; doi:10.3390/v7102894
Received: 13 August 2015 / Revised: 17 October 2015 / Accepted: 18 October 2015 / Published: 26 October 2015
Cited by 1 | PDF Full-text (1586 KB) | HTML Full-text | XML Full-text
Abstract
The Sabin I poliovirus live, attenuated vaccine strain encodes for four amino acid changes (i.e., D53N, Y73H, K250E, and T362I) in the RNA-dependent RNA polymerase (RdRp). We have previously shown that the T362I substitution leads to a lower fidelity RdRp, and viruses encoding
[...] Read more.
The Sabin I poliovirus live, attenuated vaccine strain encodes for four amino acid changes (i.e., D53N, Y73H, K250E, and T362I) in the RNA-dependent RNA polymerase (RdRp). We have previously shown that the T362I substitution leads to a lower fidelity RdRp, and viruses encoding this variant are attenuated in a mouse model of poliovirus. Given these results, it was surprising that the nucleotide incorporation rate and nucleobase fidelity of the Sabin I RdRp is similar to that of wild-type enzyme, although the Sabin I RdRp is less selective against nucleotides with modified sugar groups. We suggest that the other Sabin amino acid changes (i.e., D53N, Y73H, K250E) help to re-establish nucleotide incorporation rates and nucleotide discrimination near wild-type levels, which may be a requirement for the propagation of the virus and its efficacy as a vaccine strain. These results also suggest that the nucleobase fidelity of the Sabin I RdRp likely does not contribute to viral attenuation. Full article
Open AccessArticle Amino Terminal Region of Dengue Virus NS4A Cytosolic Domain Binds to Highly Curved Liposomes
Viruses 2015, 7(7), 4119-4130; doi:10.3390/v7072812
Received: 30 April 2015 / Revised: 10 July 2015 / Accepted: 13 July 2015 / Published: 21 July 2015
Cited by 2 | PDF Full-text (618 KB) | HTML Full-text | XML Full-text
Abstract
Dengue virus (DENV) is an important human pathogen causing millions of disease cases and thousands of deaths worldwide. Non-structural protein 4A (NS4A) is a vital component of the viral replication complex (RC) and plays a major role in the formation of host cell
[...] Read more.
Dengue virus (DENV) is an important human pathogen causing millions of disease cases and thousands of deaths worldwide. Non-structural protein 4A (NS4A) is a vital component of the viral replication complex (RC) and plays a major role in the formation of host cell membrane-derived structures that provide a scaffold for replication. The N-terminal cytoplasmic region of NS4A(1–48) is known to preferentially interact with highly curved membranes. Here, we provide experimental evidence for the stable binding of NS4A(1–48) to small liposomes using a liposome floatation assay and identify the lipid binding sequence by NMR spectroscopy. Mutations L6E;M10E were previously shown to inhibit DENV replication and to interfere with the binding of NS4A(1–48) to small liposomes. Our results provide new details on the interaction of the N-terminal region of NS4A with membranes and will prompt studies of the functional relevance of the curvature sensitive membrane anchor at the N-terminus of NS4A. Full article
Open AccessArticle Hydrogen Peroxide Induce Human Cytomegalovirus Replication through the Activation of p38-MAPK Signaling Pathway
Viruses 2015, 7(6), 2816-2833; doi:10.3390/v7062748
Received: 17 April 2015 / Accepted: 26 May 2015 / Published: 4 June 2015
Cited by 6 | PDF Full-text (2043 KB) | HTML Full-text | XML Full-text
Abstract
Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H2O2,
[...] Read more.
Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H2O2, the most common reactive oxygen species, is the main byproduct of oxidative metabolism. However, the function of H2O2 on HCMV infection is not yet fully understood and the effect and mechanism of N-acetylcysteine (NAC) on H2O2-stimulated HCMV replication is unclear. We, therefore, examined the effect of NAC on H2O2-induced HCMV production in human foreskin fibroblast cells. In the present study, we found that H2O2 enhanced HCMV lytic replication through promoting major immediate early (MIE) promoter activity and immediate early (IE) gene transcription. Conversely, NAC inhibited H2O2-upregulated viral IE gene expression and viral replication. The suppressive effect of NAC on CMV in an acute CMV-infected mouse model also showed a relationship between antioxidants and viral lytic replication. Intriguingly, the enhancement of HCMV replication via supplementation with H2O2 was accompanied with the activation of the p38 mitogen-activated protein kinase pathway. Similar to NAC, the p38 inhibitor SB203580 inhibited H2O2-induced p38 phosphorylation and HCMV upregulation, while upregulation of inducible ROS was unaffected. These results directly relate HCMV replication to H2O2, suggesting that treatment with antioxidants may be an attractive preventive and therapeutic strategy for HCMV. Full article
Open AccessArticle Both ERK1 and ERK2 Are Required for Enterovirus 71 (EV71) Efficient Replication
Viruses 2015, 7(3), 1344-1356; doi:10.3390/v7031344
Received: 13 February 2015 / Revised: 12 March 2015 / Accepted: 17 March 2015 / Published: 20 March 2015
Cited by 5 | PDF Full-text (1084 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
It has been demonstrated that MEK1, one of the two MEK isoforms in Raf-MEK-ERK1/2 pathway, is essential for successful EV71 propagation. However, the distinct function of ERK1 and ERK2 isoforms, the downstream kinases of MEKs, remains unclear in EV71 replication. In this study,
[...] Read more.
It has been demonstrated that MEK1, one of the two MEK isoforms in Raf-MEK-ERK1/2 pathway, is essential for successful EV71 propagation. However, the distinct function of ERK1 and ERK2 isoforms, the downstream kinases of MEKs, remains unclear in EV71 replication. In this study, specific ERK siRNAs and selective inhibitor U0126 were applied. Silencing specific ERK did not significantly impact on the EV71-caused biphasic activation of the other ERK isoform, suggesting the EV71-induced activations of ERK1 and ERK2 were non-discriminative and independent to one another. Knockdown of either ERK1 or ERK2 markedly impaired progeny EV71 propagation (both by more than 90%), progeny viral RNA amplification (either by about 30% to 40%) and protein synthesis (both by around 70%), indicating both ERK1 and ERK2 were critical and not interchangeable to EV71 propagation. Moreover, suppression of EV71 replication by inhibiting both early and late phases of ERK1/2 activation showed no significant difference from that of only blocking the late phase, supporting the late phase activation was more importantly responsible for EV71 life cycle. Taken together, this study for the first time identified both ERK1 and ERK2 were required for EV71 efficient replication and further verified the important role of MEK1-ERK1/2 in EV71 replication. Full article

Review

Jump to: Research

Open AccessReview The Role of Electron Microscopy in Studying the Continuum of Changes in Membranous Structures during Poliovirus Infection
Viruses 2015, 7(10), 5305-5318; doi:10.3390/v7102874
Received: 2 July 2015 / Revised: 1 September 2015 / Accepted: 23 September 2015 / Published: 12 October 2015
Cited by 2 | PDF Full-text (2992 KB) | HTML Full-text | XML Full-text
Abstract
Replication of the poliovirus genome is localized to cytoplasmic replication factories that are fashioned out of a mixture of viral proteins, scavenged cellular components, and new components that are synthesized within the cell due to viral manipulation/up-regulation of protein and phospholipid synthesis. These
[...] Read more.
Replication of the poliovirus genome is localized to cytoplasmic replication factories that are fashioned out of a mixture of viral proteins, scavenged cellular components, and new components that are synthesized within the cell due to viral manipulation/up-regulation of protein and phospholipid synthesis. These membranous replication factories are quite complex, and include markers from multiple cytoplasmic cellular organelles. This review focuses on the role of electron microscopy in advancing our understanding of poliovirus RNA replication factories. Structural data from the literature provide the basis for interpreting a wide range of biochemical studies that have been published on virus-induced lipid biosynthesis. In combination, structural and biochemical experiments elucidate the dramatic membrane remodeling that is a hallmark of poliovirus infection. Temporal and spatial membrane modifications throughout the infection cycle are discussed. Early electron microscopy studies of morphological changes following viral infection are re-considered in light of more recent data on viral manipulation of lipid and protein biosynthesis. These data suggest the existence of distinct subcellular vesicle populations, each of which serves specialized roles in poliovirus replication processes. Full article
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Open AccessReview Anti-HBV Drugs: Progress, Unmet Needs, and New Hope
Viruses 2015, 7(9), 4960-4977; doi:10.3390/v7092854
Received: 30 April 2015 / Revised: 18 August 2015 / Accepted: 24 August 2015 / Published: 15 September 2015
Cited by 14 | PDF Full-text (1875 KB) | HTML Full-text | XML Full-text
Abstract
Approximately 240 million people worldwide are chronically infected with hepatitis B virus (HBV), which represents a significant challenge to public health. The current goal in treating chronic HBV infection is to block progression of HBV-related liver injury and inflammation to end-stage liver diseases,
[...] Read more.
Approximately 240 million people worldwide are chronically infected with hepatitis B virus (HBV), which represents a significant challenge to public health. The current goal in treating chronic HBV infection is to block progression of HBV-related liver injury and inflammation to end-stage liver diseases, including cirrhosis and hepatocellular carcinoma, because we are unable to eliminate chronic HBV infection. Available therapies for chronic HBV infection mainly include nucleos/tide analogues (NAs), non-NAs, and immunomodulatory agents. However, none of them is able to clear chronic HBV infection. Thus, a new generation of anti-HBV drugs is urgently needed. Progress has been made in the development and testing of new therapeutics against chronic HBV infection. This review aims to summarize the state of the art in new HBV drug research and development and to forecast research and development trends and directions in the near future. Full article
Open AccessReview Flaviviral Replication Complex: Coordination between RNA Synthesis and 5’-RNA Capping
Viruses 2015, 7(8), 4640-4656; doi:10.3390/v7082837
Received: 30 June 2015 / Revised: 30 July 2015 / Accepted: 4 August 2015 / Published: 13 August 2015
Cited by 15 | PDF Full-text (1890 KB) | HTML Full-text | XML Full-text
Abstract
Genome replication in flavivirus requires (—) strand RNA synthesis, (+) strand RNA synthesis, and 5’-RNA capping and methylation. To carry out viral genome replication, flavivirus assembles a replication complex, consisting of both viral and host proteins, on the cytoplasmic side of the endoplasmic
[...] Read more.
Genome replication in flavivirus requires (—) strand RNA synthesis, (+) strand RNA synthesis, and 5’-RNA capping and methylation. To carry out viral genome replication, flavivirus assembles a replication complex, consisting of both viral and host proteins, on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. Two major components of the replication complex are the viral non-structural (NS) proteins NS3 and NS5. Together they possess all the enzymatic activities required for genome replication, yet how these activities are coordinated during genome replication is not clear. We provide an overview of the flaviviral genome replication process, the membrane-bound replication complex, and recent crystal structures of full-length NS5. We propose a model of how NS3 and NS5 coordinate their activities in the individual steps of (—) RNA synthesis, (+) RNA synthesis, and 5’-RNA capping and methylation. Full article
Open AccessReview Replication and Inhibitors of Enteroviruses and Parechoviruses
Viruses 2015, 7(8), 4529-4562; doi:10.3390/v7082832
Received: 1 May 2015 / Accepted: 3 August 2015 / Published: 10 August 2015
Cited by 20 | PDF Full-text (2741 KB) | HTML Full-text | XML Full-text
Abstract
The Enterovirus (EV) and Parechovirus genera of the picornavirus family include many important human pathogens, including poliovirus, rhinovirus, EV-A71, EV-D68, and human parechoviruses (HPeV). They cause a wide variety of diseases, ranging from a simple common cold to life-threatening diseases such as encephalitis
[...] Read more.
The Enterovirus (EV) and Parechovirus genera of the picornavirus family include many important human pathogens, including poliovirus, rhinovirus, EV-A71, EV-D68, and human parechoviruses (HPeV). They cause a wide variety of diseases, ranging from a simple common cold to life-threatening diseases such as encephalitis and myocarditis. At the moment, no antiviral therapy is available against these viruses and it is not feasible to develop vaccines against all EVs and HPeVs due to the great number of serotypes. Therefore, a lot of effort is being invested in the development of antiviral drugs. Both viral proteins and host proteins essential for virus replication can be used as targets for virus inhibitors. As such, a good understanding of the complex process of virus replication is pivotal in the design of antiviral strategies goes hand in hand with a good understanding of the complex process of virus replication. In this review, we will give an overview of the current state of knowledge of EV and HPeV replication and how this can be inhibited by small-molecule inhibitors. Full article
Open AccessReview The Virus-Host Interplay: Biogenesis of +RNA Replication Complexes
Viruses 2015, 7(8), 4385-4413; doi:10.3390/v7082825
Received: 16 June 2015 / Revised: 21 July 2015 / Accepted: 24 July 2015 / Published: 6 August 2015
Cited by 6 | PDF Full-text (401 KB) | HTML Full-text | XML Full-text
Abstract
Positive-strand RNA (+RNA) viruses are an important group of human and animal pathogens that have significant global health and economic impacts. Notable members include West Nile virus, Dengue virus, Chikungunya, Severe acute respiratory syndrome (SARS) Coronavirus and enteroviruses of the Picornaviridae family.Unfortunately, prophylactic
[...] Read more.
Positive-strand RNA (+RNA) viruses are an important group of human and animal pathogens that have significant global health and economic impacts. Notable members include West Nile virus, Dengue virus, Chikungunya, Severe acute respiratory syndrome (SARS) Coronavirus and enteroviruses of the Picornaviridae family.Unfortunately, prophylactic and therapeutic treatments against these pathogens are limited. +RNA viruses have limited coding capacity and thus rely extensively on host factors for successful infection and propagation. A common feature among these viruses is their ability to dramatically modify cellular membranes to serve as platforms for genome replication and assembly of new virions. These viral replication complexes (VRCs) serve two main functions: To increase replication efficiency by concentrating critical factors and to protect the viral genome from host anti-viral systems. This review summarizes current knowledge of critical host factors recruited to or demonstrated to be involved in the biogenesis and stabilization of +RNA virus VRCs. Full article
Open AccessReview RNA-Dependent RNA Polymerases of Picornaviruses: From the Structure to Regulatory Mechanisms
Viruses 2015, 7(8), 4438-4460; doi:10.3390/v7082829
Received: 11 June 2015 / Revised: 24 July 2015 / Accepted: 29 July 2015 / Published: 6 August 2015
Cited by 9 | PDF Full-text (2514 KB) | HTML Full-text | XML Full-text
Abstract
RNA viruses typically encode their own RNA-dependent RNA polymerase (RdRP) to ensure genome replication within the infected cells. RdRP function is critical not only for the virus life cycle but also for its adaptive potential. The combination of low fidelity of replication and
[...] Read more.
RNA viruses typically encode their own RNA-dependent RNA polymerase (RdRP) to ensure genome replication within the infected cells. RdRP function is critical not only for the virus life cycle but also for its adaptive potential. The combination of low fidelity of replication and the absence of proofreading and excision activities within the RdRPs result in high mutation frequencies that allow these viruses a rapid adaptation to changing environments. In this review, we summarize the current knowledge about structural and functional aspects on RdRP catalytic complexes, focused mainly in the Picornaviridae family. The structural data currently available from these viruses provided high-resolution snapshots for a range of conformational states associated to RNA template-primer binding, rNTP recognition, catalysis and chain translocation. As these enzymes are major targets for the development of antiviral compounds, such structural information is essential for the design of new therapies. Full article
Open AccessReview Translational Control of the HIV Unspliced Genomic RNA
Viruses 2015, 7(8), 4326-4351; doi:10.3390/v7082822
Received: 18 May 2015 / Revised: 18 May 2015 / Accepted: 17 July 2015 / Published: 4 August 2015
Cited by 9 | PDF Full-text (2111 KB) | HTML Full-text | XML Full-text
Abstract
Post-transcriptional control in both HIV-1 and HIV-2 is a highly regulated process that commences in the nucleus of the host infected cell and finishes by the expression of viral proteins in the cytoplasm. Expression of the unspliced genomic RNA is particularly controlled at
[...] Read more.
Post-transcriptional control in both HIV-1 and HIV-2 is a highly regulated process that commences in the nucleus of the host infected cell and finishes by the expression of viral proteins in the cytoplasm. Expression of the unspliced genomic RNA is particularly controlled at the level of RNA splicing, export, and translation. It appears increasingly obvious that all these steps are interconnected and they result in the building of a viral ribonucleoprotein complex (RNP) that must be efficiently translated in the cytosolic compartment. This review summarizes our knowledge about the genesis, localization, and expression of this viral RNP. Full article
Open AccessReview Using the Hepatitis C Virus RNA-Dependent RNA Polymerase as a Model to Understand Viral Polymerase Structure, Function and Dynamics
Viruses 2015, 7(7), 3974-3994; doi:10.3390/v7072808
Received: 30 April 2015 / Revised: 13 July 2015 / Accepted: 13 July 2015 / Published: 17 July 2015
Cited by 10 | PDF Full-text (2899 KB) | HTML Full-text | XML Full-text
Abstract
Viral polymerases replicate and transcribe the genomes of several viruses of global health concern such as Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Ebola virus. For this reason they are key targets for therapies to treat viral infections. Although there is
[...] Read more.
Viral polymerases replicate and transcribe the genomes of several viruses of global health concern such as Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Ebola virus. For this reason they are key targets for therapies to treat viral infections. Although there is little sequence similarity across the different types of viral polymerases, all of them present a right-hand shape and certain structural motifs that are highly conserved. These features allow their functional properties to be compared, with the goal of broadly applying the knowledge acquired from studying specific viral polymerases to other viral polymerases about which less is known. Here we review the structural and functional properties of the HCV RNA-dependent RNA polymerase (NS5B) in order to understand the fundamental processes underlying the replication of viral genomes. We discuss recent insights into the process by which RNA replication occurs in NS5B as well as the role that conformational changes play in this process. Full article
Open AccessReview Modes of Human T Cell Leukemia Virus Type 1 Transmission, Replication and Persistence
Viruses 2015, 7(7), 3603-3624; doi:10.3390/v7072793
Received: 30 April 2015 / Revised: 22 June 2015 / Accepted: 1 July 2015 / Published: 7 July 2015
Cited by 9 | PDF Full-text (404 KB) | HTML Full-text | XML Full-text
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes cancer (Adult T cell Leukemia, ATL) and a spectrum of inflammatory diseases (mainly HTLV-associated myelopathy—tropical spastic paraparesis, HAM/TSP). Since virions are particularly unstable, HTLV-1 transmission primarily occurs by transfer of a
[...] Read more.
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes cancer (Adult T cell Leukemia, ATL) and a spectrum of inflammatory diseases (mainly HTLV-associated myelopathy—tropical spastic paraparesis, HAM/TSP). Since virions are particularly unstable, HTLV-1 transmission primarily occurs by transfer of a cell carrying an integrated provirus. After transcription, the viral genomic RNA undergoes reverse transcription and integration into the chromosomal DNA of a cell from the newly infected host. The virus then replicates by either one of two modes: (i) an infectious cycle by virus budding and infection of new targets and (ii) mitotic division of cells harboring an integrated provirus. HTLV-1 replication initiates a series of mechanisms in the host including antiviral immunity and checkpoint control of cell proliferation. HTLV-1 has elaborated strategies to counteract these defense mechanisms allowing continuous persistence in humans. Full article
Open AccessReview Coordinated DNA Replication by the Bacteriophage T4 Replisome
Viruses 2015, 7(6), 3186-3200; doi:10.3390/v7062766
Received: 11 May 2015 / Revised: 12 June 2015 / Accepted: 16 June 2015 / Published: 19 June 2015
Cited by 4 | PDF Full-text (448 KB) | HTML Full-text | XML Full-text
Abstract
The T4 bacteriophage encodes eight proteins, which are sufficient to carry out coordinated leading and lagging strand DNA synthesis. These purified proteins have been used to reconstitute DNA synthesis in vitro and are a well-characterized model system. Recent work on the T4 replisome
[...] Read more.
The T4 bacteriophage encodes eight proteins, which are sufficient to carry out coordinated leading and lagging strand DNA synthesis. These purified proteins have been used to reconstitute DNA synthesis in vitro and are a well-characterized model system. Recent work on the T4 replisome has yielded more detailed insight into the dynamics and coordination of proteins at the replication fork. Since the leading and lagging strands are synthesized in opposite directions, coordination of DNA synthesis as well as priming and unwinding is accomplished by several protein complexes. These protein complexes serve to link catalytic activities and physically tether proteins to the replication fork. Essential to both leading and lagging strand synthesis is the formation of a holoenzyme complex composed of the polymerase and a processivity clamp. The two holoenzymes form a dimer allowing the lagging strand polymerase to be retained within the replisome after completion of each Okazaki fragment. The helicase and primase also form a complex known as the primosome, which unwinds the duplex DNA while also synthesizing primers on the lagging strand. Future studies will likely focus on defining the orientations and architecture of protein complexes at the replication fork. Full article
Open AccessReview HIV Rev Assembly on the Rev Response Element (RRE): A Structural Perspective
Viruses 2015, 7(6), 3053-3075; doi:10.3390/v7062760
Received: 8 May 2015 / Accepted: 5 June 2015 / Published: 12 June 2015
Cited by 14 | PDF Full-text (1212 KB) | HTML Full-text | XML Full-text
Abstract
HIV-1 Rev is an ~13 kD accessory protein expressed during the early stage of virus replication. After translation, Rev enters the nucleus and binds the Rev response element (RRE), a ~350 nucleotide, highly structured element embedded in the env gene in unspliced and
[...] Read more.
HIV-1 Rev is an ~13 kD accessory protein expressed during the early stage of virus replication. After translation, Rev enters the nucleus and binds the Rev response element (RRE), a ~350 nucleotide, highly structured element embedded in the env gene in unspliced and singly spliced viral RNA transcripts. Rev-RNA assemblies subsequently recruit Crm1 and other cellular proteins to form larger complexes that are exported from the nucleus. Once in the cytoplasm, the complexes dissociate and unspliced and singly-spliced viral RNAs are packaged into nascent virions or translated into viral structural proteins and enzymes, respectively. Rev binding to the RRE is a complex process, as multiple copies of the protein assemble on the RNA in a coordinated fashion via a series of Rev-Rev and Rev-RNA interactions. Our understanding of the nature of these interactions has been greatly advanced by recent studies using X-ray crystallography, small angle X-ray scattering (SAXS) and single particle electron microscopy as well as biochemical and genetic methodologies. These advances are discussed in detail in this review, along with perspectives on development of antiviral therapies targeting the HIV-1 RRE. Full article
Open AccessReview APOBEC3 Interference during Replication of Viral Genomes
Viruses 2015, 7(6), 2999-3018; doi:10.3390/v7062757
Received: 29 April 2015 / Revised: 26 May 2015 / Accepted: 4 June 2015 / Published: 11 June 2015
Cited by 10 | PDF Full-text (1142 KB) | HTML Full-text | XML Full-text
Abstract
Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission. In response, infected hosts have developed strategies of defense that counteract the deleterious effects of viral infections. In particular, single-strand DNA editing by
[...] Read more.
Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission. In response, infected hosts have developed strategies of defense that counteract the deleterious effects of viral infections. In particular, single-strand DNA editing by Apolipoprotein B Editing Catalytic subunits proteins 3 (APOBEC3s) is a well-conserved mechanism of mammalian innate immunity that mutates and inactivates viral genomes. In this review, we describe the mechanisms of APOBEC3 editing during viral replication, the viral strategies that prevent APOBEC3 activity and the consequences of APOBEC3 modulation on viral fitness and host genome integrity. Understanding the mechanisms involved reveals new prospects for therapeutic intervention. Full article
Open AccessReview HIV-1 Replication and the Cellular Eukaryotic Translation Apparatus
Viruses 2015, 7(1), 199-218; doi:10.3390/v7010199
Received: 4 November 2014 / Accepted: 12 January 2015 / Published: 19 January 2015
Cited by 13 | PDF Full-text (1790 KB) | HTML Full-text | XML Full-text
Abstract
Eukaryotic translation is a complex process composed of three main steps: initiation, elongation, and termination. During infections by RNA- and DNA-viruses, the eukaryotic translation machinery is used to assure optimal viral protein synthesis. Human immunodeficiency virus type I (HIV-1) uses several non-canonical pathways
[...] Read more.
Eukaryotic translation is a complex process composed of three main steps: initiation, elongation, and termination. During infections by RNA- and DNA-viruses, the eukaryotic translation machinery is used to assure optimal viral protein synthesis. Human immunodeficiency virus type I (HIV-1) uses several non-canonical pathways to translate its own proteins, such as leaky scanning, frameshifting, shunt, and cap-independent mechanisms. Moreover, HIV-1 modulates the host translation machinery by targeting key translation factors and overcomes different cellular obstacles that affect protein translation. In this review, we describe how HIV-1 proteins target several components of the eukaryotic translation machinery, which consequently improves viral translation and replication. Full article
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