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Jiachen Zang, Hai Chen, Xiaorong Zhang, Chenxi Zhang, Jing Guo, Ming Du, Guanghua Zhao
Constructing different protein nanostructures with high-order discrete architectures by using one single building block remains a challenge. Here, we present a simple, effective disulfide-mediated approach to prepare a set of protein nanocages with different geometries from single building block. By genetically deleting an inherent intra-subunit disulfide bond, we can render the conversion of an 8-mer bowl-like protein architecture (NF-8) into a 24-mer ferritin-like nanocage in solution, while selective insertion of an inter-subunit disulfide bond into NF-8 triggers its conversion into a 16-mer lenticular nanocage...
February 15, 2019: Nature Communications
Marcelo M Samsa, Lesley C Dupuy, Clayton W Beard, Carolyn M Six, Connie S Schmaljohn, Peter W Mason, Andrew J Geall, Jeffrey B Ulmer, Dong Yu
Venezuelan equine encephalitis virus (VEEV) is a known biological defense threat. A live-attenuated investigational vaccine, TC-83, is available, but it has a high non-response rate and can also cause severe reactogenicity. We generated two novel VEE vaccine candidates using self-amplifying mRNA (SAM). LAV-CNE is a live-attenuated VEE SAM vaccine formulated with synthetic cationic nanoemulsion (CNE) and carrying the RNA genome of TC-83. IAV-CNE is an irreversibly-attenuated VEE SAM vaccine formulated with CNE, delivering a TC-83 genome lacking the capsid gene...
January 7, 2019: Molecular Therapy: the Journal of the American Society of Gene Therapy
Marine Perrier, Louise Castain, Leslie Regad, Eve Todesco, Roland Landman, Benoit Visseaux, Yazdan Yazdanpanah, Christophe Rodriguez, Véronique Joly, Vincent Calvez, Anne-Geneviève Marcelin, Diane Descamps, Charlotte Charpentier
OBJECTIVES: To assess, at ART initiation, the impact of baseline substitutions in protease, Gag and gp41 regions on the virological response to a first-line PI-based regimen. PATIENTS AND METHODS: One hundred and fifty-four HIV-infected ART-naive patients initiating a PI-based regimen including darunavir (n = 129) or atazanavir (n = 25) were assessed, including 36 experiencing virological failure (VF). Whole pol, gag and gp41 genes were sequenced at ART baseline by ultra-deep sequencing (UDS) using Illumina® technology...
February 14, 2019: Journal of Antimicrobial Chemotherapy
D Denning, S Bennett, T Mullen, C Moyer, D Vorselen, G J L Wuite, G Nemerow, W H Roos
The ability of adenoviruses to infect a broad range of species has spurred a growing interest in nanomedicine to use adenovirus as a cargo delivery vehicle. While successful maturation of adenovirus and controlled disassembly are critical for efficient infection, the underlying mechanisms regulating these processes are not well understood. Here, we present Atomic Force Microscopy nanoindentation and fatigue studies of adenovirus capsids at different maturation stages to scrutinize their dynamic uncoating properties...
February 15, 2019: Nanoscale
Julia Fakhiri, Marc A Schneider, Jens Puschhof, Megan Stanifer, Verena Schildgen, Stefan Holderbach, Yannik Voss, Jihad El Andari, Oliver Schildgen, Steeve Boulant, Michael Meister, Hans Clevers, Ziying Yan, Jianming Qiu, Dirk Grimm
Parvoviruses are highly attractive templates for the engineering of safe, efficient, and specific gene therapy vectors, as best exemplified by adeno-associated virus (AAV). Another candidate that currently garners increasing attention is human bocavirus 1 (HBoV1). Notably, HBoV1 capsids can cross-package recombinant (r)AAV2 genomes, yielding rAAV2/HBoV1 chimeras that specifically transduce polarized human airway epithelia (pHAEs). Here, we largely expanded the repertoire of rAAV/BoV chimeras, by assembling packaging plasmids encoding the capsid genes of four additional primate bocaviruses, HBoV2-4 and GBoV (Gorilla BoV)...
March 15, 2019: Molecular Therapy. Methods & Clinical Development
Corinna Pietsch, Uwe G Liebert
BACKGROUND: Sapovirus is a common cause of self-limiting diarrhea. In immunocompromised individuals chronic infections occur, but are incompletely investigated. OBJECTIVES: To investigate viral evolution in immunocompromised hosts during chronic sapovirus infection. STUDY DESIGN: From January 2010 to September 2018 stool samples of 5333 in-patients were analyzed for the presence of sapovirus RNA by real-time RT-PCR. In follow-up samples of chronic diarrhea cases nucleic acid sequencing of sapovirus genomes was performed...
February 7, 2019: Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology
Yameng Pei, Chunting Wang, Haijing Ben, Lei Wang, Yao Ma, Qingyan Ma, Ye Xiang, Linqi Zhang, Gang Liu
In this article, a simple and effective high-throughput screening (HTS) assay was developed to identify anti-HBV compounds by using a HepAD38 luciferase reporter (HepAD38-luc) cell line that can effectively exclude the false positive hit compounds targeted on the tetracycline off (tet-off) regulation system. Through screening in-house chemical libraries, N-phenylpiperidine-3-carboxamide derivatives, represented by 1 and 2 were identified, while the other false positive hits, i. e. quinoxaline (3) and benzothiazin (4) derivatives were simultaneously excluded...
February 14, 2019: ACS Infectious Diseases
Wei Wang, Wenchao Sun, Liang Cao, Min Zheng, Yilong Zhu, Wenjie Li, Cunxia Liu, Xinyu Zhuang, Jialiang Xing, Huijun Lu, Tingrong Luo, Ningyi Jin
BACKGROUND: Porcine circovirus type 3 (PCV3) is a single-stranded, closed circular DNA virus, which causes porcine dermatitis and nephropathy syndrome (PDNS), multisystemic inflammation, and reproductive failure. The present study aimed to investigate the seroprevalence of PCV3 in cattle (Bos taurus) in Shandong province, China, and examine its genome diversity. RESULTS: PCR amplification and sequencing showed that 74 of 213 bovine samples (34.7%) were positive for PCV3...
February 13, 2019: BMC Veterinary Research
Amitis Ramezani, Arezoo Aghakhani, Sepehr Soleymani, Anahita Bavand, Azam Bolhassani
BACKGROUND: Among different types of human papillomavirus (HPV), types 16 and 18 were known to be high-risk agents causing mainly cervical cancer. Up to now, the potential of HPV E7 protein has been proved as a diagnostic marker of cervical cancer. Moreover, the levels of anti-heat shock protein (Hsp) and anti-high mobility group box-1 (HMGB1) antibodies in cancer patients have been useful in tumor diagnosis. The goal of the present study was to determine the efficiency of the potential serologic markers including HPV E7, Hsp20, Hsp27 proteins and Hp91 peptide in Iranian HPV-exposed women, for the first time...
February 12, 2019: BMC Infectious Diseases
Daniel Oliver, Monika Michaelis, Hendrik Heinz, Victor V Volkov, Carole C Perry
Polypeptide based biosilica composites show promise as next generation multi-functional nano-platforms for diagnostics and bio-catalytic applications. Following the identification of a strong silica binder (LDHSLHS) by phage display, we conduct structural analysis of the polypeptide at the interface with amorphous silica nanoparticles in an aqueous environment. Our approach relies on modelling infrared and Raman spectral responses using predictions of molecular dynamics simulations and quantum studies of the normal modes for several potential structures...
February 12, 2019: Physical Chemistry Chemical Physics: PCCP
Ran Zhang, Lin Cao, Mengtian Cui, Zixian Sun, Mingxu Hu, Rouxuan Zhang, William Stuart, Xiaochu Zhao, Zirui Yang, Xueming Li, Yuna Sun, Shentao Li, Wei Ding, Zhiyong Lou, Zihe Rao
Adeno-associated virus (AAV) is a leading vector for virus-based gene therapy. The receptor for AAV (AAVR; also named KIAA0319L) was recently identified, and the precise characterization of AAV-AAVR recognition is in immediate demand. Taking advantage of a particle-filtering algorithm, we report here the cryo-electron microscopy structure of the AAV2-AAVR complex at 2.8 Å resolution. This structure reveals that of the five Ig-like polycystic kidney disease (PKD) domains in AAVR, PKD2 binds directly to the spike region of the AAV2 capsid adjacent to the icosahedral three-fold axis...
February 11, 2019: Nature Microbiology
Ting Pan, Yanchao Ding, Liyang Wu, Liting Liang, Xin He, Qianwen Li, Chuan Bai, Hui Zhang
The capsid assembly is an essential step for Hepatitis B Virus (HBV) life cycle and is an important target for anti-HBV drug development. In this report, we identified a hit compound with aminothiazole structure by the high throughput screening (HTS) which inhibited the interaction of HBV capsid protein within the cells. The structure hopping and SAR studies of the hit compound afforded compound 79 with potent anti-HBV replication activity and good basic drug-like properties. The working mechanism studies showed that compound 79 could bind to the similar binding site of known HBV capsid inhibitor with heteroaryldihydropyrimidine (HAP) scaffold, through similar hydrophobic interactions but with a different hydrogen bond...
February 5, 2019: European Journal of Medicinal Chemistry
Mansi Verma, Shradha Bhatnagar, Kavita Kumari, Nidhi Mittal, Shivani Sukhralia, Shruthi Gopirajan At, P S Dhanaraj, Rup Lal
Dengue is a severe emerging arthropod borne viral disease occurring globally. Around two fifths of the world's population, or up to 3.9 billion people, are at a risk of dengue infection. Infection induces a life-long protective immunity to the homologous serotype but confers only partial and transient protection against subsequent infection caused by other serotypes. Thus, there is a need for a vaccine which is capable of providing a life- long protection against all the serotypes of dengue virus. In our study, comparative genomics of Dengue virus (DENV) was conducted to explore potential candidates for novel vaccine targets...
February 7, 2019: Gene
Boyuan Song, Julian Lenhart, Vanessa Judith Flegler, Cihan Makbul, Tim Rasmussen, Bettina Böttcher
Direct electron detectors are an essential asset for the resolution revolution in electron cryo microscopy of biological objects. The direct detectors provide two modes of data acquisition; the counting mode in which single electrons are counted, and the integrating mode in which the signal that arises from the incident electrons is integrated. While counting mode leads to far higher detective quantum efficiency at all spatial frequencies, the integrating mode enables faster data acquisition at higher exposure rates...
January 28, 2019: Ultramicroscopy
Oliver W Bayfield, Evgeny Klimuk, Dennis C Winkler, Emma L Hesketh, Maria Chechik, Naiqian Cheng, Eric C Dykeman, Leonid Minakhin, Neil A Ranson, Konstantin Severinov, Alasdair C Steven, Alfred A Antson
Double-stranded DNA viruses, including bacteriophages and herpesviruses, package their genomes into preformed capsids, using ATP-driven motors. Seeking to advance structural and mechanistic understanding, we established in vitro packaging for a thermostable bacteriophage, P23-45 of Thermus thermophilus Both the unexpanded procapsid and the expanded mature capsid can package DNA in the presence of packaging ATPase over the 20 °C to 70 °C temperature range, with optimum activity at 50 °C to 65 °C. Cryo-EM reconstructions for the mature and immature capsids at 3...
February 8, 2019: Proceedings of the National Academy of Sciences of the United States of America
Immacolata Speciale, Garry A Duncan, Luca Unione, Irina V Agarkova, Domenico Garozzo, Jesús Jiménez-Barbero, Sicheng Lin, Todd L Lowary, Antonio Molinaro, Eric Noel, Maria Elena Laugieri, Michela G Tonetti, James L Van Etten, Cristina De Castro
The chlorovirus Paramecium bursaria chlorella virus 1 (PBCV-1) is a large dsDNA virus that infects the microalga Chlorella variabilis NC64A. Unlike most other viruses, PBCV-1 encodes most, if not all, of the machinery required to glycosylate its major capsid protein (MCP). The structures of the four N-linked glycans from the PBCV-1 MCP consist of nonasaccharides, and similar glycans are not found elsewhere in the three domains of life. Here, we identified the roles of three virus-encoded glycosyltransferases (GTs) that have four distinct GT activities in glycan synthesis...
February 8, 2019: Journal of Biological Chemistry
Jie Zhang, Hong Guo, Fuxian Zhang, Qingxiu Chen, Mingxian Chang, Qin Fang
Aquareoviruses contain an 11-segmented double-stranded RNA genome. Previous studies indicated that NS38, a virus-encoded putative single-stranded RNA binding protein, interacts with NS80 in viral inclusion bodies (VIBs). However, the role of NS38 in aquareovirus infection remained unclear. Here, we found that NS38 interacts with inner-capsid proteins (VP1-VP4 and VP6) and the NS80-RNA complex in both transfected and infected cells. Knockdown of NS38 by siRNAs-115/219 clearly reduced viral infection, with decreased mRNA and protein yields...
February 1, 2019: Virology
Daniela Dana Dünn-Kittenplon, Inna Kalt, Jean-Paul Moshe Lellouche, Ronit Sarid
Herpesvirus capsid assembly involves cleavage and packaging of the viral genome. The Kaposi's sarcoma-associated herpesvirus (KSHV) open reading frame 43 (orf43) encodes a putative portal protein. The portal complex functions as a gate through which DNA is packaged into the preformed procapsids, and is injected into the cell nucleus upon infection. The amino acid sequence of the portal proteins is conserved among herpesviruses. Here, we generated an antiserum to ORF43 and determined late expression kinetics of ORF43 along with its nuclear localization...
February 1, 2019: Virology
Anita Kruzik, Herwig Koppensteiner, Damir Fetahagic, Bettina Hartlieb, Sebastian Dorn, Stefan Romeder-Finger, Sogué Coulibaly, Alfred Weber, Werner Höllriegl, Frank M Horling, Friedrich Scheiflinger, Birgit M Reipert, Maurus de la Rosa
Patients with preexisting anti-adeno-associated virus 8 (AAV8) neutralizing antibodies (NAbs) are currently excluded from AAV8 gene therapy trials. Therefore, the assessment of biologically relevant AAV8-NAb titers is critical for product development in gene therapy. However, standardized assays have not been routinely used to determine anti-AAV8-NAb titers, contributing to a wide range of reported anti-AAV8 prevalences. Using a clinical in vitro NAb assay in a separate study, we found a higher than expected anti-AAV8-NAb prevalence in international cohorts of about 50%...
February 8, 2019: Human Gene Therapy Methods
Eun Byul Lee, Jung-Hee Kim, Wonhee Hur, Jung Eun Choi, Sung Min Kim, Dong Jun Park, Byung-Yoon Kang, Gil Won Lee, Seung Kew Yoon
Virus-like particles (VLPs) possess great potential for organ-specific transport of therapeutic agents due to their central cavity surrounded by viral capsid proteins and similar tropism to their original viruses. The N-terminal truncated second open reading frame (Nt-ORF2) of the hepatotropic hepatitis E virus (HEV) forms VLPs via self-assembly. In the present study, we investigated whether HEV-LPs could deliver foreign genes specifically to the liver. HEV-LPs were obtained from Nt-ORF2 expression in Huh7 cells that were transduced with recombinant baculoviruses and purified by continuous density gradient centrifugation...
February 7, 2019: Scientific Reports
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