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https://www.readbyqxmd.com/read/27935939/structural-basis-for-inhibitor-induced-aggregation-of-hiv-integrase
#1
Kushol Gupta, Vesa Turkki, Scott Sherrill-Mix, Young Hwang, Grant Eilers, Louis Taylor, Charlene McDanal, Ping Wang, David Temelkoff, Robert T Nolte, Emile Velthuisen, Jerry Jeffrey, Gregory D Van Duyne, Frederic D Bushman
The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 Å resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain...
December 2016: PLoS Biology
https://www.readbyqxmd.com/read/27934981/novel-dna-sensor-system-for-highly-sensitive-and-quantitative-retrovirus-detection-using-virus-encoded-integrase-as-a-biomarker
#2
Jing Wang, Jiangnan Liu, Jonas Thomsen, Denis Selnihhin, Marianne S Hede, Freja C M Kirsebom, Oskar Franch, Søren Fjelstrup, Magnus Stougaard, Yi-Ping Ho, Finn Skou Pedersen, Birgitta R Knudsen
In the current study we describe a novel DNA sensor system that allows the detection of single catalytic DNA integration events mediated by retrovirus encoded integrase (IN) present in viral particles. This is achieved by rolling circle amplification mediated conversion of enzymatic reactions happening within nanometer dimensions to directly detectable micrometer sized DNA products. The system utilizes the unique integration reaction of IN to generate a surface anchored nicked DNA circle that serves as a substrate for rolling circle amplification and allows for specific, quantitative and sensitive detection of purified recombinant IN or virus particles with a detection limit of less than 30 virus particles per μL of sample...
December 9, 2016: Nanoscale
https://www.readbyqxmd.com/read/27930472/risks-associated-with-lentiviral-vector-exposures-and-prevention-strategies
#3
Ryan Schlimgen, John Howard, Dawn Wooley, Maureen Thompson, Lindsey R Baden, Otto O Yang, David C Christiani, Gustavo Mostoslavsky, David V Diamond, Elizabeth Gilman Duane, Karen Byers, Thomas Winters, Jeffrey A Gelfand, Gary Fujimoto, T Warner Hudson, Jatin M Vyas
Lentiviral vectors (LVVs) are powerful genetic tools that are being used with greater frequency in biomedical laboratories and clinical trials. Adverse events reported from initial clinical studies provide a basis for risk assessment of occupational exposures, yet many questions remain about the potential harm that LVVs may cause. We review those risks and provide a framework for principal investigators, Institutional Biosafety Committees, and occupational health professionals to assess and communicate the risks of exposure to staff...
December 2016: Journal of Occupational and Environmental Medicine
https://www.readbyqxmd.com/read/27923578/characterization-of-antibiotic-resistance-genes-in-representative-organic-solid-wastes-food-waste-recycling-wastewater-manure-and-sewage-sludge
#4
Jangwoo Lee, Seung Gu Shin, Hyun Min Jang, Young Beom Kim, Joonyeob Lee, Young Mo Kim
In this research, the distribution of antibiotic resistance genes (ARGs) was characterized in representative organic solid waste (OSW) in Korea: food waste-recycling wastewater (FRW), manure, and sewage sludge. The amounts of total ARG (gene copies/16S rRNA gene copies) was greatest in manure followed by sewage sludge and FRW. Interestingly, there were significantly different patterns in the diversity and mechanisms of ARGs. For example, a significant proportion of ARGs were tetracycline resistant genes in all the OSW (40...
December 3, 2016: Science of the Total Environment
https://www.readbyqxmd.com/read/27912079/a-humanized-mouse-model-for-hiv-2-infection-and-efficacy-testing-of-a-single-pill-triple-drug-combination-anti-retroviral-therapy
#5
Shuang Hu, Charles Preston Neff, Dipu Mohan Kumar, Yuichiro Habu, Sarah R Akkina, Takahiro Seki, Ramesh Akkina
While HIV-2 is a causative agent for AIDS in addition to the better studied HIV-1, there is currently no suitable animal model for experimental studies for HIV-2 infection and evaluating promising drugs in vivo. Here we evaluated humanized mice for their susceptibility to HIV-2 infection and tested a single-pill three drug formulation of anti-retrovirals (NRTIs abacavir and lamivudine, integrase inhibitor dolutegravir) (trade name, Triumeq(R)). Our results showed that hu-mice are susceptible to HIV-2 infection showing persistent viremia and CD4 T cell loss, key hallmarks of AIDS pathogenesis...
November 29, 2016: Virology
https://www.readbyqxmd.com/read/27911725/the-multiple-roles-of-the-nucleocapsid-in-retroviral-rna-conversion-into-proviral-dna-by-reverse-transcriptase
#6
REVIEW
Jean-Luc Darlix, Hugues de Rocquigny, Yves Mély
Retroviruses are enveloped plus-strand RNA viruses that can cause cancer, immunodeficiency and neurological disorder in human and animals. Retroviruses have several unique properties, such as a genomic RNA in a dimeric form found in the virus, and a replication strategy called 'copy-and-paste' during which the plus-strand genomic RNA is converted into a double-stranded DNA, subsequently integrated into the cellular genome. Two essential viral enzymes, reverse transcriptase (RT) and integrase (IN), direct this 'copy-and-paste' replication...
October 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27910923/protein-expression-from-unintegrated-hiv-1-dna-introduces-bias-in-primary-in-vitro-post-integration-latency-models
#7
Pawel Bonczkowski, Marie-Angélique De Scheerder, Eva Malatinkova, Alexandra Borch, Zora Melkova, Renate Koenig, Ward De Spiegelaere, Linos Vandekerckhove
To understand the persistence of latently HIV-1 infected cells in virally suppressed infected patients, a number of in vitro models of HIV latency have been developed. In an attempt to mimic the in vivo situation as closely as possible, several models use primary cells and replication-competent viruses in combination with antiretroviral compounds to prevent ongoing replication. Latency is subsequently measured by HIV RNA and/or protein production after cellular activation. To discriminate between pre- and post-integration latency, integrase inhibitors are routinely used, preventing novel integrations upon cellular activation...
December 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27907973/-second-generation-integrase-inhibitors
#8
David Jilich
Antiretroviral therapy is the only effective treatment of HIV infection. Based on data demonstrating the beneficial effect of therapy in all HIV patients, the percentage of persons receiving treatment has increased in recent years. HIV integrase inhibitors play an important role in modern therapy.
September 2016: Klinická Mikrobiologie a Infekc̆ní Lékar̆ství
https://www.readbyqxmd.com/read/27905987/factors-associated-with-the-first-antiretroviral-therapy-modification-in-older-hiv-1-positive-patients
#9
Justyna D Kowalska, Joanna Kubicka, Ewa Siwak, Piotr Pulik, Ewa Firląg-Burkacka, Andrzej Horban
BACKGROUND: Rates of first antiretroviral therapy (cART) modifications are high in most observational studies. The age-related differences in treatment duration and characteristics of first cART modifications remain underinvestigated. With increasing proportion of older patients in HIV population it is important to better understand age-related treatment effects. METHODS: Patients were included into this analysis, if being cART naïve at the first visit at the clinic...
January 7, 2016: AIDS Research and Therapy
https://www.readbyqxmd.com/read/27899664/integration-defective-lentiviral-vector-mediates-efficient-gene-editing-through-homology-directed-repair-in-human-embryonic-stem-cells
#10
Yebo Wang, Yingjia Wang, Tammy Chang, He Huang, Jiing-Kuan Yee
Human embryonic stem cells (hESCs) are used as platforms for disease study, drug screening and cell-based therapy. To facilitate these applications, it is frequently necessary to genetically manipulate the hESC genome. Gene editing with engineered nucleases enables site-specific genetic modification of the human genome through homology-directed repair (HDR). However, the frequency of HDR remains low in hESCs. We combined efficient expression of engineered nucleases and integration-defective lentiviral vector (IDLV) transduction for donor template delivery to mediate HDR in hESC line WA09...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27893693/two-case-reports-of-severe-myocarditis-associated-with-the-initiation-of-dolutegravir-treatment-in-hiv-patients
#11
Keren Mahlab-Guri, Ilan Asher, Shira Rosenberg-Bezalel, Daniel Elbirt, Michael Burke, Zev M Sthoeger
RATIONALE: The integrase inhibitor dolutegravir is now recommended as first-line treatment for HIV. A single case of myocarditis after treatment with dolutegravir was reported in the FLAMINGO trial. We present here 2 cases of severe myocarditis that occurred shortly after the initiation of dolutegravir treatment. PATIENTS CONCERNS: The first case is a 45-year-old female who developed severe congestive heart failure and died, weeks after the initiation of dolutegravir treatment (for simplification of her antiretroviral regimen)...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27882352/quantitative-evaluation-of-the-antiretroviral-efficacy-of-dolutegravir
#12
Sarah B Laskey, Robert F Siliciano
The second-generation HIV-1 integrase strand transfer inhibitor (InSTI) dolutegravir (DTG) has had a major impact on the treatment of HIV-1 infection. Here we describe important but previously undetermined pharmacodynamic parameters for DTG. We show that the dose-response curve slope, which indicates cooperativity and is a major determinant of antiviral activity, is higher for DTG than for first-generation InSTIs. This steepness does not reflect inhibition of multiple steps in the HIV-1 life cycle, as is the case for allosteric integrase inhibitors and HIV-1 protease inhibitors...
November 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27864282/bxb1-integrase-serves-as-a-highly-efficient-dna-recombinase-in-rapid-metabolite-pathway-assembly
#13
Xianwei Wang, Biao Tang, Yu Ye, Yayi Mao, Xiaolai Lei, Guoping Zhao, Xiaoming Ding
Phage-encoded serine integrases are widely used in genetic engineering. They also have the potential to serve as efficient DNA assemblers, demonstrated by the method of site-specific recombination-based tandem assembly (SSRTA) that can combine biological parts into devices, pathways, and systems. Here, four serine integrases, ϕBT1, TG1, ϕRv1, and Bxb1, were investigated to ascertain their in vitro DNA assembly activities. Bxb1 integrase displayed the highest efficiency to obtain final products. Thus, we conclude that Bxb1 integrase is an excellent choice for DNA assembly in vitro Using this enzyme and its recognition sites, BioBrick standards were designed that are compatible with the SSRTA method for module addition...
November 17, 2016: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/27860104/higher-rates-of-neuropsychiatric-adverse-events-leading-to-dolutegravir-discontinuation-in-women-and-older-patients
#14
C Hoffmann, T Welz, M Sabranski, M Kolb, E Wolf, H-J Stellbrink, C Wyen
OBJECTIVES: Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among the most frequently used antiretroviral agents. However, recent reports have raised concerns about potential neurotoxicity. METHODS: We performed a retrospective analysis of a cohort of HIV-infected patients who had initiated an INSTI in two large German out-patient clinics between 2007 and 2016. We compared discontinuation rates because of adverse events (AEs) within 2 years of starting treatment with dolutegravir, raltegravir or elvitegravir/cobicistat...
January 2017: HIV Medicine
https://www.readbyqxmd.com/read/27845364/a-genomic-island-in-vibrio-cholerae-with-vpi-1-site-specific-recombination-characteristics-contains-crispr-cas-and-type-vi-secretion-modules
#15
Maurizio Labbate, Fabini D Orata, Nicola K Petty, Nathasha D Jayatilleke, William L King, Paul C Kirchberger, Chris Allen, Gulay Mann, Ankur Mutreja, Nicholas R Thomson, Yan Boucher, Ian G Charles
Cholera is a devastating diarrhoeal disease caused by certain strains of serogroup O1/O139 Vibrio cholerae. Mobile genetic elements such as genomic islands (GIs) have been pivotal in the evolution of O1/O139 V. cholerae. Perhaps the most important GI involved in cholera disease is the V. cholerae pathogenicity island 1 (VPI-1). This GI contains the toxin-coregulated pilus (TCP) gene cluster that is necessary for colonization of the human intestine as well as being the receptor for infection by the cholera-toxin bearing CTX phage...
November 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27842871/trends-in-drug-resistance-associated-mutations-in-a-real-life-cohort-of-italian-patients-infected-with-hiv-1
#16
Claudia Montagna, Laura Mazzuti, Francesca Falasca, Paola Maida, Mauro Bucci, Gabriella D'Ettorre, Ivano Mezzaroma, Alessandra Fantauzzi, Nadia Alvaro, Vincenzo Vullo, Guido Antonelli, Ombretta Turriziani
Recent studies support the idea that human immunodeficiency virus type 1 (HIV-1) drug resistance is declining in developed countries. To help assess the current situation in Italy, the dynamics of drug resistance mutations in pol and integrase genes in plasma samples from HIV-1-positive patients attending Sapienza University Hospital, Rome, from 2003 to 2014 were analysed. In total, 1730 genotype resistance tests (GRTs) were retrospectively analysed. The prevalence of major drug resistance mutations (DRMs) was evaluated over time in the global population and in patients with antiretroviral therapy (ART) failure...
December 2015: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/27835934/the-conformational-feasibility-for-the-formation-of-reaching-dimer-in-asv-and-hiv-integrase-a-molecular-dynamics-study
#17
Sangeetha Balasubramanian, Muthukumaran Rajagopalan, Ravi Shankar Bojja, Anna Marie Skalka, Mark D Andrake, Amutha Ramaswamy
Retroviral integrases are reported to form alternate dimer assemblies like the core-core dimer and reaching dimer. The core-core dimer is stabilized predominantly by an extensive interface between two catalytic core domains. The reaching dimer is stabilized by N-terminal domains (NTD) that reach to form intermolecular interfaces with the other subunit's core and C-terminal domains (CTD), as well as CTD-CTD interactions. In this study, molecular dynamics (MD), Brownian dynamics (BD) simulations, and free energy analyses, were performed to elucidate determinants for the stability of the reaching dimer forms of full-length ASV and HIV IN, and to examine the role of the C-tails (the last ~16-18 residues at the C-termini) in their structural dynamics...
November 11, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/27830755/dynamic-oligomerization-of-integrase-orchestrates-hiv-nuclear-entry
#18
Doortje Borrenberghs, Lieve Dirix, Flore De Wit, Susana Rocha, Jolien Blokken, Stéphanie De Houwer, Rik Gijsbers, Frauke Christ, Johan Hofkens, Jelle Hendrix, Zeger Debyser
Nuclear entry is a selective, dynamic process granting the HIV-1 pre-integration complex (PIC) access to the chromatin. Classical analysis of nuclear entry of heterogeneous viral particles only yields averaged information. We now have employed single-virus fluorescence methods to follow the fate of single viral pre-integration complexes (PICs) during infection by visualizing HIV-1 integrase (IN). Nuclear entry is associated with a reduction in the number of IN molecules in the complexes while the interaction with LEDGF/p75 enhances IN oligomerization in the nucleus...
November 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27829863/the-effect-of-geometrical-isomerism-of-3-5-dicaffeoylquinic-acid-on-its-binding-affinity-to-hiv-integrase-enzyme-a-molecular-docking-study
#19
Mpho M Makola, Ian A Dubery, Gerrit Koorsen, Paul A Steenkamp, Mwadham M Kabanda, Louis L du Preez, Ntakadzeni E Madala
A potent plant-derived HIV-1 inhibitor, 3,5-dicaffeoylquinic acid (diCQA), has been shown to undergo isomerisation upon UV exposure where the naturally occurring 3 (trans) ,5 (trans) -diCQA isomer gives rise to the 3 (cis) ,5 (trans) -diCQA, 3 (trans) ,5 (cis) -diCQA, and 3 (cis) ,5 (cis) -diCQA isomers. In this study, inhibition of HIV-1 INT by UV-induced isomers was investigated using molecular docking methods. Here, density functional theory (DFT) models were used for geometry optimization of the 3,5-diCQA isomers...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/27826447/experience-of-dolutegravir-in-hiv-infected-treatment-naive-patients-from-a-tertiary-care-university-hospital-in-ireland
#20
Sarmad Waqas, Mairead O'Connor, Ciara Levey, Paddy Mallon, Gerard Sheehan, Anjali Patel, Gordana Avramovic, John S Lambert
OBJECTIVE: Dolutegravir, an HIV integrase inhibitor, is a relatively new treatment option. To assess the tolerability, side effects, and time to viral decline to non-detectable in patients newly started on dolutegravir. METHODS: Retrospective health care record of 61 consecutive HIV treatment-naive patients started on dolutegravir was reviewed and analysed on SPSS. RESULTS: The mean initial viral load was 160826.05 copies/mL (range, 79-1,126,617 copies/mL)...
2016: SAGE Open Medicine
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