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https://www.readbyqxmd.com/read/28645089/drug-resistance-mechanism-of-l10f-l10f-n88s-and-l90m-mutations-in-crf01_ae-hiv-1-protease-molecular-dynamics-simulations-and-binding-free-energy-calculations
#1
C S Vasavi, Ramasamy Tamizhselvi, Punnagai Munusami
HIV-1 protease plays a crucial role in viral replication and maturation, which makes it one of the most attractive targets for anti-retroviral therapy. The majority of HIV infections in developing countries are due to non-B subtype. Subtype AE is spreading rapidly and infecting huge population worldwide. The mutations in the active site of subtype AE directly impair the interactions with the inhibitor. The non-active site mutations influence the binding of the inhibitor indirectly and their resistance mechanism is not well understood...
June 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28630490/pyroptosis-superinfection-and-the-maintenance-of-the-latent-reservoir-in-hiv-1-infection
#2
Dominik Wodarz, David N Levy
A long-lived reservoir of latently infected T cells prevents antiretroviral therapy from eliminating HIV-1 infection. Furthering our understanding of the dynamics of latency generation and maintenance is therefore vital to improve treatment outcome. Using mathematical models and experiments, we suggest that the death of latently infected cells brought about by pyroptosis, or to a lesser extent by superinfection, might be key mechanisms to account for the size and composition of the latent reservoir. Pyroptosis is a form of cell death that occurs in a resting (and thus latently infected) T cell when a productively infected cell attempts cell-to-cell transmission of virus...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28628334/chiral-indolylarylsulfone-non-nucleoside-reverse-transcriptase-inhibitors-as-new-potent-and-broad-spectrum-anti-hiv-1-agents
#3
Valeria Famiglini, Giuseppe La Regina, Antonio Coluccia, Domiziana Masci, Andrea Brancale, Roger Badia, Eva Riveira Muñoz, Jose A Este, Emmanuele Crespan, Alessandro Brambilla, Giovanni Maga, Myriam Catalano, Cristina Limatola, Francesca Romana Romana Formica, Roberto Cirilli, Ettore Novellino, Romano Silvestri
We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 8-37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L and K103N-Y181C HIV-1 strains. Six racemic mixtures, 8, 23-25, 31 and 33, were separated at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (α-methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31 and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers...
June 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28623781/inhibition-activities-of-catechol-diether-based-non-nucleoside-inhibitors-against-the-hiv-reverse-transcriptase-variants-insights-from-molecular-docking-and-oniom-calculations
#4
Pabitra Narayan Samanta, Kalyan Kumar Das
The therapeutic effectiveness of the catechol diether analogs against both the wild-type and drug-resistant reverse transcriptase (RT) mutants of HIV strains are investigated by performing molecular docking and hybrid ONIOM calculations. The docking protocol has been used to predict the binding modes of the non-nucleoside inhibitors inside the active site cavity of the viral enzymes. For each enzyme-inhibitor adduct, the predicted docked poses are assessed by employing different scoring function based programs...
June 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28623359/allosteric-modulatory-effects-of-sri-20041-and-sri-30827-on-cocaine-and-hiv-1-tat-protein-binding-to-human-dopamine-transporter
#5
Wei-Lun Sun, Pamela M Quizon, Yaxia Yuan, Wei Zhang, Subramaniam Ananthan, Chang-Guo Zhan, Jun Zhu
Dopamine transporter (DAT) is the target of cocaine and HIV-1 transactivator of transcription (Tat) protein. Identifying allosteric modulatory molecules with potential attenuation of cocaine and Tat binding to DAT are of great scientific and clinical interest. We demonstrated that tyrosine 470 and 88 act as functional recognition residues in human DAT (hDAT) for Tat-induced inhibition of DA transport and transporter conformational transitions. Here we investigated the allosteric modulatory effects of two allosteric ligands, SRI-20041 and SRI-30827 on cocaine binding on wild type (WT) hDAT, Y470 H and Y88 F mutants...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28615206/plasticity-and-epitope-exposure-of-the-hiv-1-envelope-trimer
#6
Rebecca L R Powell, Maxim Totrov, Vincenza Itri, Xiaomei Liu, Alisa Fox, Susan Zolla-Pazner
We recently showed that mutations in the HIV-1 Envelope (Env) destabilize the V3 loop, rendering neutralization-resistant viruses sensitive to V3-directed monoclonal antibodies (mAbs). Here we investigated the propagation of this effect on other Env epitopes, with special emphasis on V2 loop exposure. Wildtype JR-FL and 19 mutant JR-FL pseudoviruses were tested for neutralization sensitivity to 21 mAbs specific for epitopes in V2, the CD4 binding site (CD4bs), and the CD4-induced (CD4i) region. Certain glycan mutants, mutations in the gp120 hydrophobic core, and mutations in residues involved in intra-protomer interactions exposed epitopes in the V2i region (overlays the α4β7 integrin binding site) and the V3 crown, suggesting a general destabilization of the distal region of the trimer apex...
June 14, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28610923/l368f-v408f-double-mutant-of-ibd-of-ledgf-p75-retains-interaction-with-m178i-mutant-of-hiv-1-integrase
#7
Anu George, Nidhanapati K Raghavendra
Lens-epithelium-derived-growth factor (LEDGF/p75) is an essential host protein for integration of HIV-1 DNA into host genome. Earlier alanine scanning mutational analysis has revealed that residues I365, D366 and F406 in the integrase binding domain (IBD) of p75 are critical for interaction with HIV-1 integrase (IN), while K364, V408 have intermediate effect and residues N367, L368, R405, K407 show wild type binding with IN. To gain insight into contribution of side chains of L368 and V408 that are adjacent to critical residues I365 and F406, respectively, site directed mutation of these residues to Ile/Leu, Met and Phe has been performed and characterized in this study...
June 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28608480/sgk1-nedd4-2-signaling-pathway-regulates-the-activity-of-human-organic-anion-transporters-3
#8
Haoxun Wang, Guofeng You
Human organic anion transporter 3 (hOAT3) is localized at the basolateral membrane of renal proximal tubule cells and facilitates renal secretion of numerous clinical drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, antihypertension drugs, and anti-inflammatories. In the present study, we explored the role of serum and glucocorticoid-inducible kinase 1 (sgk1) in the regulation of hOAT3. We showed that over-expression of sgk1 in hOAT3-expressing cells stimulated hOAT3 transport activity by enhancing the transporter expression at the plasma membrane, kinetically reflected as an increased maximal transport velocity Vmax without substantial change in substrate-binding affinity Km ...
June 13, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28603746/preclinical-evaluation-of-a-lentiviral-vector-for-huntingtin-silencing
#9
Karine Cambon, Virginie Zimmer, Sylvain Martineau, Marie-Claude Gaillard, Margot Jarrige, Aurore Bugi, Jana Miniarikova, Maria Rey, Raymonde Hassig, Noelle Dufour, Gwenaelle Auregan, Philippe Hantraye, Anselme L Perrier, Nicole Déglon
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA), vectorized in an HIV-1-derived lentiviral vector (LV), that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL) backbone and removing the original reporter genes...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28589513/prevalence-of-hiv-1-transmitted-drug-resistance-in-recently-infected-treatment-na%C3%A3-ve-persons-in-the-southwest-of-iran-2014-2015
#10
Shokouh Ghafari, Arash Memarnejadian, Alireza Samarbaf-Zadeh, Ehsan Mostafavi, Manoochehr Makvandi, Shokrolah Salmanzadeh, Ata Ghadiri, Michael R Jordan, Elham Mousavi, Fatemeh Jahanbakhsh, Kayhan Azadmanesh
The emergence and transmission of drug resistant HIV mutants is a major concern, especially in resource-limited countries with expanding antiretroviral therapy. Studies have recently reported the prevalence of HIV-1 transmitted drug resistance (TDR) mutations in certain Iranian cities; however, no information is currently available about the level of TDR, as well as the nature of the circulating HIV-1 subtypes, in the Southwestern bordering province of Iran, Khuzestan. Herein, we used a WHO-recommended TDR survey method to classify the prevalence of TDR in indigenous people of Khuzestan province...
June 6, 2017: Archives of Virology
https://www.readbyqxmd.com/read/28579254/comprehensive-mapping-of-hiv-1-escape-from-a-broadly-neutralizing-antibody
#11
Adam S Dingens, Hugh K Haddox, Julie Overbaugh, Jesse D Bloom
Precisely defining how viral mutations affect HIV's sensitivity to antibodies is vital to develop and evaluate vaccines and antibody immunotherapeutics. Despite great effort, a full map of escape mutants has not been delineated for an anti-HIV antibody. We describe a massively parallel experimental approach to quantify how all single amino acid mutations to HIV Envelope (Env) affect neutralizing antibody sensitivity in the context of replication-competent virus. We apply this approach to PGT151, a broadly neutralizing antibody recognizing a combination of Env residues and glycans...
June 14, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28577469/the-interaction-between-hiv-1-nef-and-adaptor-protein-2-reduces-nef-mediated-cd4-t-cell-apoptosis
#12
Rajesh Abraham Jacob, Aaron L Johnson, Emily N Pawlak, Brennan S Dirk, Logan R Van Nynatten, S M Mansour Haeryfar, Jimmy D Dikeakos
Acquired Immune Deficiency Syndrome is characterized by a decline in CD4(+) T cells. Here, we elucidated the mechanism underlying apoptosis in Human Immunodeficiency Virus-1 (HIV-1) infection by examining host apoptotic pathways hijacked by the HIV-1 Nef protein in the CD4(+) T-cell line Sup-T1. Using a panel of Nef mutants unable to bind specific host proteins we uncovered that Nef generates pro- and anti-apoptotic signals. Apoptosis increased upon mutating the motifs involved in the interaction of Nef:AP-1 (NefM20A or NefEEEE62-65AAAA) or Nef:AP-2 (NefLL164/165AA), implying these interactions limit Nef-mediated apoptosis...
May 31, 2017: Virology
https://www.readbyqxmd.com/read/28569216/potent-and-reversible-lentiviral-vector-restriction-in-murine-induced-pluripotent-stem-cells
#13
Franziska K Geis, Melanie Galla, Dirk Hoffmann, Johannes Kuehle, Daniela Zychlinski, Tobias Maetzig, Juliane W Schott, Adrian Schwarzer, Christine Goffinet, Stephen P Goff, Axel Schambach
BACKGROUND: Retroviral vectors are derived from wild-type retroviruses, can be used to study retrovirus-host interactions and are effective tools in gene and cell therapy. However, numerous cell types are resistant or less permissive to retrovirus infection due to the presence of active defense mechanisms, or the absence of important cellular host co-factors. In contrast to multipotent stem cells, pluripotent stem cells (PSC) have potential to differentiate into all three germ layers...
May 31, 2017: Retrovirology
https://www.readbyqxmd.com/read/28559249/mk-8591-4-ethynyl-2-fluoro-2-deoxyadenosine-exhibits-potent-activity-against-hiv-2-isolates-and-drug-resistant-hiv-2-mutants-in-culture
#14
Vincent H Wu, Robert A Smith, Sara Masoum, Dana N Raugi, Selly Ba, Moussa Seydi, Jay A Grobler, Geoffrey S Gottlieb
There is a pressing need to identify more effective antiretroviral drugs for HIV-2 treatment. Here, we show the investigational compound MK-8591 (4' -ethynyl-2-fluoro-2' -deoxyadenosine; EFdA) is highly active against group A and B isolates of HIV-2; 50% effective concentrations [EC50] for HIV-2 were, on average, 4.8-fold lower than those observed for HIV-1. MK-8591 also retains potent activity against multinucleoside-resistant HIV-2 mutants (EC50 ≤11 nM). These data suggest that MK-8591 may have antiviral activity in HIV-2-infected individuals...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28530637/cell-penetrating-peptides-selectively-targeting-smad3-inhibit-profibrotic-tgf-%C3%AE-signaling
#15
Jeong-Han Kang, Mi-Yeon Jung, Xueqian Yin, Mahefatiana Andrianifahanana, Danielle M Hernandez, Edward B Leof
TGF-β is considered a master switch in the pathogenesis of organ fibrosis. The primary mediators of this activity are the SMAD proteins, particularly SMAD3. In the current study, we have developed a cell-penetrating peptide (CPP) conjugate of the HIV TAT protein that is fused to an aminoterminal sequence of sorting nexin 9 (SNX9), which was previously shown to bind phosphorylated SMAD3 (pSMAD3). We determined that specifically preventing the nuclear import of pSMAD3 using the TAT-SNX9 peptide inhibited profibrotic TGF-β activity in murine cells and human lung fibroblasts as well as in vivo with no demonstrable toxicity...
May 22, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28525359/i36t%C3%A2-t-mutation-in-south-african-subtype-c-c-sa-hiv-1-protease-significantly-alters-protease-drug-interactions
#16
Sibusiso B Maseko, Eden Padayachee, Thavendran Govender, Yasien Sayed, Gert Kruger, Glenn E M Maguire, Johnson Lin
The efficacy of HIV-1 protease inhibition therapies is often compromised by the emergence of mutations in the protease molecule that reduces the binding affinity of inhibitors while maintaining viable catalytic activity and affinity for natural substrates. In the present study, we used a recombinant HIV-1 C-SA protease and a recently reported variant for inhibition (Ki, IC50) and thermodynamic studies against nine clinically used inhibitors. This is the first time that binding free energies for C-SA PR and the mutant are reported...
May 19, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28516844/clues-for-two-step-virion-infectivity-factor-regulation-by-core-binding-factor-beta
#17
Youwei Ai, Jianzhang Ma, Xiaojun Wang
Lentiviruses threaten human and animal health. Virion infectivity factor (Vif) is essential for the infectivity of most lentiviruses, except for the equine infectious anaemia virus (EIAV). Vif promotes viral infectivity by recruiting a Cullin-based E3 ligase to induce the degradation of a class of host restriction factors, named APOBEC3. Core binding factor beta (CBF-β) is necessary for several primate lentiviral Vif functions, including HIV-1 Vif. Although much progress has been made in understanding the contribution of CBF-β to Vif function, the precise mechanism has not yet been fully elucidated...
May 18, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28505418/how-mutations-can-resist-drug-binding-yet-keep-hiv-1-protease-functional
#18
Rajeswari Appadurai, Sanjib Senapati
Human immunodeficiency virus-1 (HIV-1) protease is an important drug target for acquired immune deficiency syndrome therapy. Nearly 10 small molecule drugs have been approved by the Food and Drug Administration (FDA). However, prolonged use of these drugs produced protease mutants that are not susceptible to many of these drugs. The mutated proteases, however, continue to cleave the substrate peptides and thus remain largely functional. This poses a major challenge for the treatment strategies. Thus, it has become imperative to understand how these mutations induce drug resistance while maintaining the enzymatic activity of this protein...
June 1, 2017: Biochemistry
https://www.readbyqxmd.com/read/28497977/effect-of-amino-acid-substitutions-within-the-v3-region-of-hiv-1-crf01_ae-on-interaction-with-ccr5-coreceptor
#19
Sayamon Hongjaisee, Martine Braibant, Francis Barin, Nicole Ngo-Giang-Huong, Wasna Sirirungsi, Tanawan Samleerat
Specific amino acids within the V3 loop of HIV-1 CRF01_AE envelope glycoprotein that are involved in the interaction with CCR5/CXCR4 coreceptors, are not well characterized. We generated V3 mutants using polymerase chain reaction (PCR)-based site-directed mutagenesis of HIV-1 CRF01_AE R5-env plasmids at specific positions. Mutant viruses were produced by env-pseudotyped virus assay, tested for coreceptor usage using U373.R5 and U373.X4 cells, and viral entry was assessed with luciferase activity measurement...
June 12, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28481112/structure-based-optimization-of-thiophene-3-2-d-pyrimidine-derivatives-as-potent-hiv-1-non-nucleoside-reverse-transcriptase-inhibitors-with-improved-potency-against-resistance-associated-variants
#20
Dongwei Kang, Zengjun Fang, Boshi Huang, Xueyi Lu, Heng Zhang, Haoran Xu, Zhipeng Huo, Zhongxia Zhou, Zhao Yu, Qing Meng, Gaochan Wu, Xiao Ding, Ye Tian, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016 , 59 , 7991 - 8007 ). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells...
May 25, 2017: Journal of Medicinal Chemistry
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