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https://www.readbyqxmd.com/read/28530637/cell-penetrating-peptides-selectively-targeting-smad3-inhibit-profibrotic-tgf-%C3%AE-signaling
#1
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
#2
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
#3
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
#4
Rajeswari Appadurai, Sanjib Senapati
HIV-1 protease is an important drug target for AIDS therapy. Nearly ten small molecule drugs have been approved by FDA. However, prolonged usage of these drugs produced protease mutants that are insusceptible 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 in the treatment strategies. Thus it has become imperative to understand how these mutations induce drug resistance while maintaining the enzymatic activity of this protein...
May 15, 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
#5
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 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. All viruses, harboring either single or double mutations, used the CCR5 coreceptor...
May 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
#6
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 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28468838/hiv-1-tat-potently-stabilizes-mdm2-and-enhances-viral-replication
#7
Rameez Raja, Larance Ronsard, Sneh Lata, Shubhendu Trivedi, Akhil C Banerjea
Murine double minute 2 (Mdm2) is known to enhance the transactivation potential of human immunodeficiency virus (HIV-1) Tat protein by ubiquitinating it. However, the regulation of Mdm2 during HIV-1 infection and its implications on viral replication have not been well studied. Here, we show that the Mdm2 protein level increases during HIV-1 infection and this effect is mediated by HIV-1 Tat protein. Tat appears to stabilise Mdm2 at the post-translational level by inducing its phosphorylation at serine-166 position through AKT...
May 3, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28465101/drug-like-property-driven-optimization-of-4-substituted-1-5-diarylanilines-as-potent-hiv-1-non-nucleoside-reverse-transcriptase-inhibitors-against-rilpivirine-resistant-mutant-virus
#8
Lei Wei, Hui-Ling Wang, Li Huang, Chin-Ho Chen, Susan L Morris-Natschke, Kuo-Hsiung Lee, Lan Xie
On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R(1)) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R(1) side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma...
April 22, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28446620/how-to-win-the-hiv-1-drug-resistance-hurdle-race-running-faster-or-jumping-higher
#9
REVIEW
Anna Garbelli, Valentina Riva, Emmanuele Crespan, Giovanni Maga
Infections by the human immunodeficiency virus type 1 (HIV-1), the causative agent of the acquired immunodeficiency syndrome (AIDS), are still totaling an appalling 36.7 millions worldwide, with 1.1 million AIDS deaths/year and a similar number of yearly new infections. All this, in spite of the discovery of HIV-1 as the AIDS etiological agent more than 30 years ago and the introduction of an effective combinatorial antiretroviral therapy (cART), able to control disease progression, more than 20 years ago. Although very effective, current cART is plagued by the emergence of drug-resistant viral variants and most of the efforts in the development of novel direct-acting antiviral agents (DAAs) against HIV-1 have been devoted toward the fighting of resistance...
April 26, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28442603/aspergillus-fumigatus-trehalose-regulatory-subunit-homolog-moonlights-to-mediate-cell-wall-homeostasis-through-modulation-of-chitin-synthase-activity
#10
Arsa Thammahong, Alayna K Caffrey-Card, Sourabh Dhingra, Joshua J Obar, Robert A Cramer
Trehalose biosynthesis is found in fungi but not humans. Proteins involved in trehalose biosynthesis are essential for fungal pathogen virulence in humans and plants through multiple mechanisms. Loss of canonical trehalose biosynthesis genes in the human pathogen Aspergillus fumigatus significantly alters cell wall structure and integrity, though the mechanistic link between these virulence-associated pathways remains enigmatic. Here we characterize genes, called tslA and tslB, which encode proteins that contain domains similar to those corresponding to trehalose-6-phosphate phosphatase but lack critical catalytic residues for phosphatase activity...
April 25, 2017: MBio
https://www.readbyqxmd.com/read/28439409/serial-deletion-reveals-structural-basis-and-stability-for-the-core-enzyme-activity-of-human-glutaminase-1-isoforms-relevance-to-excitotoxic-neurodegeneration
#11
Yuju Li, Justin Peer, Runze Zhao, Yinghua Xu, Beiqing Wu, Yi Wang, Changhai Tian, Yunlong Huang, Jialin Zheng
BACKGROUND: Glutaminase 1 is a phosphate-activated metabolic enzyme that catalyzes the first step of glutaminolysis, which converts glutamine into glutamate. Glutamate is the major neurotransmitter of excitatory synapses, executing important physiological functions in the central nervous system. There are two isoforms of glutaminase 1, KGA and GAC, both of which are generated through alternative splicing from the same gene. KGA and GAC both transcribe 1-14 exons in the N-terminal, but each has its unique C-terminal in the coding sequence...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/28426273/preclinical-development-of-bcg-hiva-2auxo-int-harboring-an-integrative-expression-vector-for-a-hiv-tb-pediatric-vaccine-enhancement-of-stability-and-specific-hiv-1-t-cell-immunity
#12
Aakash Mahant, Narcís Saubi, Yoshiki Eto, Núria Guitart, Josep M ª Gatell, Tomáš Hanke, Joan Joseph
One of the critical issues that should be addressed in the development of a BCG-based HIV vaccine is genetic plasmid stability. Therefore, to address this issue we have considered using integrative vectors and the auxotrophic mutant of BCG complemented with a plasmid carrying a wild-type complementing gene. In this study, we have constructed an integrative E. coli-mycobacterial shuttle plasmid, p2auxo.HIVA(int), expressing the HIV-1 clade A immunogen HIVA. This shuttle vector employs an antibiotic resistance-free mechanism for plasmid selection and maintenance...
April 20, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28424288/virion-associated-vpr-alleviates-a-post-integration-block-to-hiv-1-infection-of-dendritic-cells
#13
Caitlin M Miller, Hisashi Akiyama, Luis M Agosto, Ann Emery, Chelsea R Ettinger, Ronald I Swamstrom, Andrew J Henderson, Suryaram Gummuluru
Viral protein R (Vpr) is an HIV-1 accessory protein whose function remains poorly understood. In this report, we sought to determine the requirement of Vpr in facilitating HIV-1 infection of monocyte-derived dendritic cells (MDDCs), one of the first cells to encounter virus in the peripheral mucosal tissues. We characterize in this report a significant restriction to Vpr-deficient virus replication and spread in MDDCs alone and in cell-to-cell spread in MDDC - CD4(+) T cell co-cultures. This restriction to HIV-1 replication in MDDCs was observed in a single round of virus replication and was rescued by expression of Vpr in trans in the incoming virion...
April 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28424281/distinct-roles-of-vaccinia-virus-nf-kb-inhibitor-proteins-a52-b15-and-k7-in-the-immune-response
#14
Mauro Di Pilato, Ernesto Mejías-Pérez, Carlos Oscar S Sorzano, Mariano Esteban
Poxviruses use a complex strategy to escape immune control, by expressing immunomodulatory proteins that could limit their use as vaccine vectors. To test the role of poxvirus NF-κB pathway inhibitors A52, B15 and K7 in immunity, we deleted their genes in a NYVAC vaccinia virus strain that expresses HIV-1 clade C antigens. After infection of mice, ablation of A52R, B15R and K7R increased dendritic cell, natural killer cell and neutrophil migration as well as chemokine/cytokine expression. Revertant viruses for these genes confirmed their role in inhibiting the innate immune system...
April 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28392143/development-of-a-dna-vaccine-expressing-a-secreted-hiv-1-gp41-ectodomain-that-includes-the-membrane-proximal-external-region
#15
Luca Melnychuk, Lara Ajamian, Patrick Jean-Pierre, Jiaming Liang, Romina Gheorghe, Mark A Wainberg, Gerasimos J Zaharatos
A limited number of sites on the HIV-1 Envelope protein are vulnerable to broadly neutralizing antibodies (bnAbs). One of these sites, the membrane proximal external region (MPER), is located at the C-terminus of the gp41 ectodomain (gp41ecto). This highly conserved sequence is bound by several well-characterized bnAbs. Efforts to produce a gp41 immunogen are in part hampered by the MPER's hydrophobicity and propensity to induce aggregation. We sought to produce a DNA vaccine expressing a gp41ecto that is both secreted from mammalian cells and maintains binding by bnAbs to the MPER...
May 9, 2017: Vaccine
https://www.readbyqxmd.com/read/28390939/guanine-%C3%AE-carboxy-nucleoside-phosphonate-g-%C3%AE-cnp-shows-a-different-inhibitory-kinetic-profile-against-the-dna-polymerases-of-human-immunodeficiency-virus-hiv-and-herpes-viruses
#16
Jan Balzarini, Michael Menni, Kalyan Das, Lizette van Berckelaer, Alan Ford, Nuala M Maguire, Sandra Liekens, Paul E Boehmer, Eddy Arnold, Matthias Götte, Anita R Maguire
α-Carboxy nucleoside phosphonates (α-CNPs) are modified nucleotides that represent a novel class of nucleotide-competing reverse transcriptase (RT) inhibitors (NcRTIs). They were designed to act directly against HIV-1 RT without the need for prior activation (phosphorylation). In this respect, they differ from the nucleoside or nucleotide RTIs [N(t)RTIs] that require conversion to their triphosphate forms before being inhibitory to HIV-1 RT. The guanine derivative (G-α-CNP) has now been synthesized and investigated for the first time...
April 6, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28388673/proteolysis-of-mature-hiv-1-p6-gag-protein-by-the-insulin-degrading-enzyme-ide-regulates-virus-replication-in-an-env-dependent-manner
#17
Friedrich Hahn, Adrian Schmalen, Christian Setz, Melanie Friedrich, Stefan Schlößer, Julia Kölle, Robert Spranger, Pia Rauch, Kirsten Fraedrich, Tatjana Reif, Julia Karius-Fischer, Ashok Balasubramanyam, Petra Henklein, Torgils Fossen, Ulrich Schubert
There is a significantly higher risk for type II diabetes in HIV-1 carriers, albeit the molecular mechanism for this HIV-related pathology remains enigmatic. The 52 amino acid HIV-1 p6 Gag protein is synthesized as the C-terminal part of the Gag polyprotein Pr55. In this context, p6 promotes virus release by its two late (L-) domains, and facilitates the incorporation of the viral accessory protein Vpr. However, the function of p6 in its mature form, after proteolytic release from Gag, has not been investigated yet...
2017: PloS One
https://www.readbyqxmd.com/read/28381554/dna-mutagenic-activity-and-capacity-for-hiv-1-restriction-of-the-cytidine-deaminase-apobec3g-depends-on-whether-dna-or-rna-binds-to-tyrosine-315
#18
Bogdan Polevoda, Rebecca Joseph, Alan E Friedman, Ryan P Bennett, Rebecca Greiner, Thareendra De Zoysa, Ryan A Stewart, Harold C Smith
APOBEC3G (A3G) belongs to the AID/APOBEC protein family of cytidine deaminases (CDA) that bind to nucleic acids. A3G mutates the HIV genome by deamination of dC to dU, leading to accumulation of virus-inactivating mutations. Binding to cellular RNAs inhibits A3G binding to substrate single-stranded (ss) DNA and CDA activity. RNA and ssDNA bind to the same three A3G tryptic peptides (amino acids 181-194, 314-320, and 345-374) that form parts of a continuously exposed protein surface extending from the catalytic domain in the C-terminus of A3G to its N-terminus...
April 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28379444/a-dead-box-protein-acts-through-rna-to-promote-hiv-1-rev-rre-assembly
#19
Rajan Lamichhane, John A Hammond, Raymond F Pauszek, Rae M Anderson, Ingemar Pedron, Edwin van der Schans, James R Williamson, David P Millar
The HIV-1 Rev protein activates nuclear export of unspliced and partially spliced viral RNA transcripts, which encode the viral genome and the genes encoding viral structural proteins, by binding to and oligomerizing on the Rev Response Element (RRE). The human DEAD-box protein 1 (DDX1) enhances the RNA export activity of Rev through an unknown mechanism. Using a single-molecule assembly assay and various DDX1 mutants, we show that DDX1 acts through the RRE RNA to specifically accelerate the nucleation step of the Rev-RRE assembly process...
May 5, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28377526/the-r263k-dolutegravir-resistance-associated-substitution-progressively-decreases-hiv-1-integration
#20
Thibault Mesplède, Jing Leng, Hanh Thi Pham, Jiaming Liang, Yudong Quan, Yingshan Han, Mark A Wainberg
Human immunodeficiency virus (HIV) infection persists despite decades of active antiretroviral therapy (ART), effectively preventing viral eradication. Treatment decreases plasma viral RNA, but viral DNA persists, mostly integrated within the genome of nucleated blood cells. Viral DNA blood levels correlate with comorbidities and the rapidity of viral rebound following treatment interruption. To date, no intervention aiming at decreasing HIV DNA levels below those attained through ART has been successful. This includes use of some integrase inhibitors either as part of ART or in treatment intensification studies...
April 4, 2017: MBio
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