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Charlotte Charpentier, Diane Descamps
The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated mutations: R263K and E157Q. The R263K mutation was the first mutation rarely found selected at time of virological failure in patients failing a first-line dolutegravir-based treatment. Further in vitro studies on R263K mutants showed a moderate increase in phenotypic resistance level and a drastic reduction in viral replicative capacity...
January 18, 2018: Viruses
Francois Parant, Patrick Miailhes, Florence Brunel, Marie-Claude Gagnieu
Dolutegravir (DTG), a highly effective second-generation HIV integrase inhibitor with high genetic barrier to resistance, has shown excellent tolerability and safety profiles in clinical trials. However, some patients may experience neurological or psychiatric adverse effects leading to DTG discontinuation. This report describes a case of 29-year-old woman who developed neurological adverse events after starting the DTG-based antiretroviral therapy. Serum DTG concentrations were supra-therapeutic which has required a dosing interval adjustment...
January 16, 2018: Current Drug Safety
Charlotte Charpentier, Isabelle Malet, Elisabeth Andre-Garnier, Alexandre Storto, Laurence Bocket, Corinne Amiel, Laurence Morand-Joubert, Camille Tumiotto, Thuy Nguyen, Anne Maillard, Audrey Rodallec, Marie Leoz, Brigitte Montes, Véronique Schneider, Jean-Christophe Plantier, Julia Dina, Coralie Pallier, Audrey Mirand, Catherine Roussel, Anne Signori-Schmuck, Stéphanie Raymond, Vincent Calvez, Constance Delaugerre, Anne-Geneviève Marcelin, Diane Descamps
Objectives: To assess the phenotypic susceptibility of the E157Q polymorphism in HIV-1 integrase (IN) and the virological outcome of patients infected with E157Q-mutated virus initiating an IN inhibitor (INI)-based regimen. Methods: This was a multicentre study assessing IN sequences from INI-naive patients among 17 French HIV clinical centres. E157Q site-directed mutants in pNL4.3 and pCRF02_AG contexts were assessed in a recombinant phenotypic assay. Results: Prevalence of the E157Q polymorphism was 2...
January 12, 2018: Journal of Antimicrobial Chemotherapy
Kirsten A Veldsman, Jean Maritz, Shahieda Isaacs, Mary Grace Katusiime, Anita Janse Van Rensburg, Barbara Laughton, John W Mellors, Mark F Cotton, Gert U van Zyl
OBJECTIVE: Birth diagnosis of HIV-1 infection offers an ideal opportunity for early antiretroviral treatment (ART) to limit HIV-1 reservoir size and limit disease progression. Although data on cellular HIV-1 DNA decay exist for children commencing treatment from 2-3 months of age, data is lacking for starting shortly after birth. DESIGN: We studied infants who initiated ART within 8 days after birth to assess HIV-1 DNA levels longitudinally. METHODS: Children were recruited from public health clinics in Cape Town where birth diagnosis of HIV-1 coupled with early ART initiation occurred...
January 13, 2018: AIDS
Aditya Jagarapu, LaMont Cannon, Ryan Zurakowski
The recent introduction of integrase inhibitors to the HIV antiviral repertoire permits us to create in vitro experiments that reliably terminate HIV infection at the point of chromosomal integration. This allows us to isolate the dynamics of a single round of infection, without needing to account for the influence of multiple overlapping rounds of infection. By measuring the various nucleic acid concentrations in a population of infected target cells at multiple time points, we can infer the rates of these molecular events with great accuracy, which allows us to compare the rates between target cells with different functional phenotypes...
May 2017: Proceedings of the ... American Control Conference
Jonas Demeulemeester, Jolien Blokken, Stéphanie De Houwer, Lieve Dirix, Hugo Klaassen, Arnaud Marchand, Patrick Chaltin, Frauke Christ, Zeger Debyser
BACKGROUND: Combination antiretroviral therapy efficiently suppresses HIV replication in infected patients, transforming HIV/AIDS into a chronic disease. Viral resistance does develop however, especially under suboptimal treatment conditions such as poor adherence. As a consequence, continued exploration of novel targets is paramount to identify novel antivirals that do not suffer from cross-resistance with existing drugs. One new promising class of targets are HIV protein-cofactor interactions...
January 12, 2018: Retrovirology
Peter J Veldkamp, John W Mellors, Elias K Halvas
No abstract text is available yet for this article.
January 8, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Christine Merrick, Jia Zhao, Susan Rosser
Serine integrases catalyze precise rearrangement of DNA through site-specific recombination of small sequences of DNA called attachment (att) sites. Unlike other site-specific recombinases, the recombination reaction driven by serine integrases is highly directional and can only be reversed in the presence of an accessory protein called a recombination directionality factor (RDF). The ability to control reaction directionality has led to the development of serine integrases as tools for controlled rearrangement and modification of DNA in synthetic biology, gene therapy, and biotechnology...
January 9, 2018: ACS Synthetic Biology
Tuan Hai Nguyen, Tho Duc Pham, Naomi Higa, Hanako Iwashita, Taichiro Takemura, Makoto Ohnishi, Kouichi Morita, Tetsu Yamashiro
Vibrio cholerae O1 El Tor, the pathogen responsible for the current cholera pandemic became pathogenic by acquiring virulent factors including Vibrio seventh pandemic islands (VSP)-I and -II. Diversity of VSP-II are well recognized, however, studies addressing attachment sequence left (attL) sequences of VSP-II are few. In this report, a wide variety of V. cholerae strains were analyzed for the structure and distribution of VSP-II in relation to their attachment sequences. Of 188 V. cholerae strains analyzed, 81% (153/188) strains carried VSP-II, of those, typical VSP-II, and a short variant was found in 36% (55/153), and 63% (96/153), respectively...
January 8, 2018: Microbiology and Immunology
Pujari Sanjay, Gaikwad S, Joshi K, Dabhade D, Sane S, Rao N, Bele V
No abstract text is available yet for this article.
January 8, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Yanmei Li, Ling Yang, Jie Fu, Muxia Yan, Dingqiang Chen, Li Zhang
Regarded as a common genetic element responsible for horizontal gene transfer and wide spread of antimicrobial resistance among a large variety of bacteria, integrons are commonly distributed and considered as a determinant in the acquisition and evolution of virulence and antibiotic resistance. To date, the surveillances of integrons have been widely conducted in clinic, community even husbandry. For exact and accurate integron screening, as well as resistant cassettes, reliable monitoring methods is need...
January 3, 2018: Microbial Pathogenesis
Axel Fun, Thomas Leitner, Linos Vandekerckhove, Martin Däumer, Alexander Thielen, Bernd Buchholz, Andy I M Hoepelman, Elizabeth H Gisolf, Pauline J Schipper, Annemarie M J Wensing, Monique Nijhuis
BACKGROUND: Emergence of resistance against integrase inhibitor raltegravir in human immunodeficiency virus type 1 (HIV-1) patients is generally associated with selection of one of three signature mutations: Y143C/R, Q148K/H/R or N155H, representing three distinct resistance pathways. The mechanisms that drive selection of a specific pathway are still poorly understood. We investigated the impact of the HIV-1 genetic background and population dynamics on the emergence of raltegravir resistance...
January 5, 2018: Retrovirology
Chinmay Vijay Tikhe, Chris R Gissendanner, Claudia Husseneder
We isolated and sequenced the novel Enterobacter bacteriophage Arya from termite gut. The genome showed synteny to lytic bacteriophage genomes; however, the genome encodes a truncated, putatively nonfunctional integrase pseudogene. Lysogeny-related genes were previously observed in certain lytic phages, but their role and evolution remain unclear.
January 4, 2018: Genome Announcements
María Carla Martini, María Paula Quiroga, Mariano Pistorio, Antonio Lagares, Daniela Centrón, María Florencia Del Papa
Rapid dissemination and emergence of novel antibiotic resistance genes among bacteria are rising problems worldwide. Since their discovery in clinical isolates in the late 1980s, class 1 integrons have been found in a wide range of bacterial genera and have been extensively studied as contributors to dissemination of antibiotic resistance.The present study aimed to investigate the presence and structure of class 1 integrons in plasmid-carrying bacterial isolates obtained from a biopurification system used for decontamination of pesticide-contaminated water as well as their possible role as reservoir of antimicrobial-resistance gene cassettes...
December 27, 2017: FEMS Microbiology Ecology
Yanzhen Bi, Zaidong Hua, Hongyan Ren, Liping Zhang, Hongwei Xiao, Ximei Liu, Wenjun Hua, Shuqi Mei, Adrian Molenaar, Götz Laible, Xinmin Zheng
Programmable nucleases have allowed the rapid development of gene editing and transgenics, but the technology still suffers from the lack of predefined genetic loci for reliable transgene expression and maintenance. To address this issue, we used ФC31 integrase to navigate the porcine genome and identify the pseudo attP sites suitable as safe harbors for sustained transgene expression. The combined ФC31 integrase mRNA and an enhanced green fluorescence protein (EGFP) reporter donor were microinjected into one-cell zygotes for transgene integration...
January 4, 2018: International Journal of Molecular Sciences
Miguel A Lopez, Randi M Mackler, Matthew P Altman, Kristine E Yoder
The integrase (IN) protein of the retrovirus prototype foamy virus (PFV) is a model enzyme for studying the mechanism of retroviral integration. Compared to IN from other retroviruses, PFV IN is more soluble and more amenable to experimental manipulation. Additionally, it is sensitive to clinically relevant human immunodeficiency virus (HIV-1) IN inhibitors, suggesting that the catalytic mechanism of PFV IN is similar to that of HIV-1 IN. IN catalyzes the covalent joining of viral complementary DNA (cDNA) to target DNA in a process called strand transfer...
December 8, 2017: Journal of Visualized Experiments: JoVE
Sriram Vijayraghavan, Boris Kantor
Lentiviral vectors are an ideal choice for delivering gene-editing components to cells due to their capacity for stably transducing a broad range of cells and mediating high levels of gene expression. However, their ability to integrate into the host cell genome enhances the risk of insertional mutagenicity and thus raises safety concerns and limits their usage in clinical settings. Further, the persistent expression of gene-editing components delivered by these integration-competent lentiviral vectors (ICLVs) increases the probability of promiscuous gene targeting...
December 12, 2017: Journal of Visualized Experiments: JoVE
Andrew M Hill, Nikkita Mitchell, Sophie Hughes, Anton L Pozniak
PURPOSE OF REVIEW: Results from nonrandomized cohort studies suggest higher risks of CNS adverse events for dolutegravir, versus other ARVs. There have been two case reports of myocarditis on dolutegravir. Integrase inhibitors have been associated with IRIS in two cohort studies. Meta-analysis of randomized trials can be used to cross-check potential safety signals. This systematic review of drug safety used an EMBASE and MEDLINE search combined with serious adverse event (SAE) reports on the website www...
December 22, 2017: Current Opinion in HIV and AIDS
Chyi-Liang Chen, Lin-Hui Su, Rajendra Prasad Janapatla, Chun-Yen Lin, Cheng-Hsun Chiu
BACKGROUND: Zoonotic Salmonella enterica serovar Choleraesuis (S. Choleraesuis), causing paratyphoid in pigs and bacteremia in humans, commonly carry a virulence plasmid and sometimes a separate antimicrobial-resistant plasmid or merging together. This study aimed to analyze the likely mechanism of how to form a virulence-resistance chimera of plasmid in S. Choleraesuis. METHODS: Whole plasmid sequence of pOU7519 in S. Choleraesuis strain OU7519 was determined using shotgun cloning and sequencing...
December 14, 2017: Journal of Microbiology, Immunology, and Infection, Wei Mian Yu Gan Ran za Zhi
Paweł Wawrzyniak, Grażyna Płucienniczak, Dariusz Bartosik
Horizontal gene transfer (HGT) contributes greatly to the plasticity and evolution of prokaryotic and eukaryotic genomes. The main carriers of foreign DNA in HGT are mobile genetic elements (MGEs) that have extremely diverse genetic structures and properties. Various strategies are used for the maintenance and spread of MGEs, including (i) vegetative replication, (ii) transposition (and other types of recombination), and (iii) conjugal transfer. In many MGEs, all of these processes are dependent on rolling-circle replication (RCR)...
2017: Frontiers in Microbiology
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