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https://www.readbyqxmd.com/read/28202766/inhibition-of-hiv-1-maturation-via-small-molecule-targeting-of-the-amino-terminal-domain-in-the-viral-capsid-protein
#1
Weifeng Wang, Jing Zhou, Upul D Halambage, Kellie A Jurado, Augusta V Jamin, Yujie Wang, Alan N Engelman, Christopher Aiken
The HIV-1 capsid protein is an attractive therapeutic target owing to its multifunctionality in virus replication and the high fitness cost of amino acid substitutions in capsid to HIV-1 infectivity. To date, small molecule inhibitors have been identified that inhibit HIV-1 capsid assembly and/or impair its function in target cells. Here we describe the mechanism of action of the previously reported capsid-targeting HIV-1 inhibitor, BI compound 1 (C1). We show that C1 acts during HIV-1 maturation to prevent assembly of a mature viral capsid...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28202754/jak-stat-signaling-pathways-and-inhibitors-affect-reversion-of-envelope-mutated-hiv-1
#2
Yudong Quan, Hongtao Xu, Yingshan Han, Thibault Mesplède, Mark A Wainberg
HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that numerous of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, followed by reversion to wild type. However, the activation of JAK-STAT signaling pathways caused inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in ability to bind to the CD4 receptor...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28195728/room-temperature-neutron-crystallography-of-drug-resistant-hiv-1-protease-uncovers-limitations-of-x-ray-structural-analysis-at-100k
#3
Oksana O Gerlits, David A Keen, Matthew P Blakeley, John M Louis, Irene T Weber, Andrey Y Kovalevsky
HIV-1 protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 protease, we used room-temperature joint X-ray/Neutron (XN) crystallography to obtain an atomic-resolution structure of the protease triple mutant (V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals a D+ ion located midway between the inner Oδ1 oxygen atoms of the catalytic aspartic acid residues...
February 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28161890/homology-guided-mutational-analysis-reveals-the-functional-requirements-for-antinociceptive-specificity-of-crmp2-derived-peptides
#4
Aubin Moutal, Wennan Li, Yue Wang, Weina Ju, Shizhen Luo, Song Cai, Liberty François-Moutal, Samantha Perez-Miller, Jackie Hu, Erik T Dustrude, Todd W Vanderah, Vijay Gokhale, May Khanna, Rajesh Khanna
BACKGROUND AND PURPOSE: N-type voltage-gated calcium (CaV2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Despite CaV2.2 antagonism being recommended as first-line treatment for neuropathic pain, calcium-current blocking gabapentinoids inadequately alleviate chronic pain symptoms and are often mired by numerous side-effects. Collapsin response mediator protein 2 (CRMP2) targets CaV2.2 to the sensory neuron membrane, and allosterically modulates Cav2...
February 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28152383/htlv-1-tax-activates-hiv-1-transcription-in-latency-models
#5
Victor Emmanuel Viana Geddes, Diego Pandeló José, Fabio E Leal, Douglas F Nixon, Amilcar Tanuri, Renato Santana Aguiar
HIV-1 latency is a major obstacle to HIV-1 eradication. Coinfection with HTLV-1 has been associated with faster progression to AIDS. HTLV-1 encodes the transactivator Tax which can activate both HTLV-1 and HIV-1 transcription. Here, we demonstrate that Tax activates HIV transcription in latent CD4(+) T cells. Tax promotes the activation of P-TEFb, releasing CDK9 and Cyclin T1 from inactive forms, promoting transcription elongation and reactivation of latent HIV-1. Tax mutants lacking interaction with the HIV-1-LTR promoter were not able to activate P-TEFb, with no subsequent activation of latent HIV...
January 30, 2017: Virology
https://www.readbyqxmd.com/read/28134256/the-tumour-suppressor-apc-promotes-hiv-1-assembly-via-interaction-with-gag-precursor-protein
#6
Kei Miyakawa, Mayuko Nishi, Satoko Matsunaga, Akiko Okayama, Masaki Anraku, Ayumi Kudoh, Hisashi Hirano, Hirokazu Kimura, Yuko Morikawa, Naoki Yamamoto, Akira Ono, Akihide Ryo
Diverse cellular proteins and RNAs are tightly regulated in their subcellular localization to exert their local function. Here we report that the tumour suppressor adenomatous polyposis coli protein (APC) directs the localization and assembly of human immunodeficiency virus (HIV)-1 Gag polyprotein at distinct membrane components to enable the efficient production and spread of infectious viral particles. A proteomic analysis and subsequent biomolecular interaction assay reveals that the carboxyl terminus of APC interacts with the matrix region of Gag...
January 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28133802/antibody-virus-co-evolution-in-hiv-infection-paths-for-hiv-vaccine-development
#7
REVIEW
Mattia Bonsignori, Hua-Xin Liao, Feng Gao, Wilton B Williams, S Munir Alam, David C Montefiori, Barton F Haynes
Induction of HIV-1 broadly neutralizing antibodies (bnAbs) to date has only been observed in the setting of HIV-1 infection, and then only years after HIV transmission. Thus, the concept has emerged that one path to induction of bnAbs is to define the viral and immunologic events that occur during HIV-1 infection, and then to mimic those events with a vaccine formulation. This concept has led to efforts to map both virus and antibody events that occur from the time of HIV-1 transmission to development of bnAbs...
January 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28125233/depth-dependent-membrane-ordering-by-hemagglutinin-fusion-peptide-promotes-fusion
#8
Hirak Chakraborty, Barry R Lentz, Mamata Kombrabail, G Krishnamoorthy, Amitabha Chattopadhyay
Membrane fusion, one of the most fundamental processes in life, occurs when two separate lipid membranes merge into a single continuous bilayer. Membrane fusion is essential for the entry of lipid-sheathed viruses such as influenza and HIV. Influenza virus is internalized via receptor-mediated endocytosis and then fuses with the endosomal membrane at low pH. Hemagglutinin, a glycoprotein found on the surface of influenza virus, is responsible for the fusion of the viral sheath with the endosomal membrane. The ∼20 amino acid long N-terminus of hemagglutinin, known as the fusion peptide, plays a crucial role in the viral fusion process...
February 9, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28121713/a-novel-hiv-1-gp41-tripartite-model-for-rational-design-of-hiv-1-fusion-inhibitors-with-improved-antiviral-activity
#9
Shan Su, Qian Wang, Wei Xu, Fei Yu, Chen Hua, Yun Zhu, Shibo Jiang, Lu Lu
OBJECTIVES: During HIV-1 fusion process, the N-terminal heptad repeat (NHR) of the HIV-1 gp41 interacts with the C-terminal heptad repeat (CHR) to form the fusion active 6-helix bundle (6-HB), thus being an effective target for the design of CHR-peptide-based HIV-1 fusion inhibitors. To overcome the limitations of the simplified helix wheel model of 6-HB, we herein developed a novel HIV-1 gp41 NHR-CHR-NHR tripartite model for the rational design of HIV-1 fusion inhibitors with improved antiviral activities...
January 24, 2017: AIDS
https://www.readbyqxmd.com/read/28106981/controlling-multi-cycle-replication-of-live-attenuated-hiv-1-using-an-unnatural-genetic-switch
#10
Zhe Yuan, Nanxi Wang, Guobin Kang, Wei Niu, Qingsheng Li, Jiantao Guo
A safe and effective human immunodeficiency virus type 1 (HIV-1) vaccine is urgently needed, but remains elusive. While HIV-1 live-attenuated vaccine can provide potent protection as demonstrated in rhesus macaque-simian immunodeficiency virus model, the potential pathogenic consequences associated with the uncontrolled virus replication preclude such vaccine from clinical applications. We investigated a novel approach to address this problem by controlling live-attenuated HIV-1 replication through an unnatural genetic switch that was based on the amber suppression strategy...
January 20, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28056217/zinc-binding-site-of-hiv-2-vpx-prevents-instability-and-dysfunction-of-the-protein
#11
Minami Yamamoto, Ryoko Koga, Haruna Fujino, Kazunori Shimagaki, Halil Ibrahim Ciftci, Masahiro Kamo, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita
HIV-2 Vpx coordinates zinc through residues H39, H82, C87 and C89. We reported previously that H39, H82 and C87 mutants maintain Vpx activity to facilitate the degradation of SAMHD1. Herein, the expression of Vpx mutants in cells was examined in detail. We demonstrated that the zinc-binding site stabilizes the protein to keep its function in virus growth when low levels of Vpx are expressed. At higher levels of expression, Vpx aggregation can occur, and zinc binding would suppress such aggregation. Among the amino acids involved in zinc coordination, H39 plays the most critical role...
January 5, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28032867/regulation-of-er-stress-induced-autophagy-by-gsk3%C3%AE-tip60-ulk1-pathway
#12
Tiejian Nie, Shaosong Yang, Hongwei Ma, Lei Zhang, Fangfang Lu, Kai Tao, Ronglin Wang, Ruixin Yang, Lu Huang, Zixu Mao, Qian Yang
Endoplasmic reticulum (ER) stress is involved in many cellular processes. Emerging evidence suggests that ER stress can trigger autophagy; however, the mechanisms by which ER stress regulates autophagy and its role in this condition are not fully understood. HIV Tat-interactive protein, 60 kDa (TIP60) is a newly discovered acetyltransferase that can modulate autophagy flux by activating ULK1 upon growth factor deprivation. In this study, we investigated the mechanisms by which ER stress induces autophagy...
December 29, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/28031466/cell-based-fluorescence-complementation-reveals-a-role-for-hiv-1-nef-dimerization-in-ap-2-recruitment-and-cd4-downregulation
#13
Sherry T Shu, Lori A Emert-Sedlak, Thomas E Smithgall
The HIV-1 Nef accessory factor enhances viral infectivity, immune evasion, and AIDS progression. Nef triggers rapid downregulation of CD4 via the endocytic adaptor protein 2 (AP-2) complex, a process linked to enhanced viral infectivity and immune escape. Here we describe a bimolecular fluorescence complementation (BiFC) assay to visualize the interaction of Nef with AP-2 and CD4 in living cells. Interacting protein pairs were fused to complementary, non-fluorescent fragments of YFP and co-expressed in 293T cells...
December 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28031368/the-structural-interface-between-hiv-1-vif-and-human-apobec3h
#14
Marcel Ooms, Michael Letko, Viviana Simon
: Human APOBEC3H (A3H) is a cytidine deaminase that inhibits HIV-1 replication. To evade this restriction, the HIV-1 Vif protein binds A3H and mediates its proteasomal degradation. To date, little information on the Vif-A3H interface is available. To decipher how both proteins interact we first mapped the Vif-binding site on A3H by functionally testing a large set of A3H mutants in single cycle infectivity and replication assays. Our data show that the two A3H α-helixes α3 and α4 represent the Vif-binding site of A3H...
December 28, 2016: Journal of Virology
https://www.readbyqxmd.com/read/28002960/characterization-of-new-cationic-n-n-dimethyl-70-fulleropyrrolidinium-iodide-derivatives-as-potent-hiv-1-maturation-inhibitors
#15
Edison Castro, Zachary S Martinez, Chang-Soo Seong, Andrea Cabrera-Espinoza, Mauro Ruiz, Andrea Hernandez Garcia, Federico Valdez, Manuel Llano, Luis Echegoyen
HIV-1 maturation can be impaired by altering protease (PR) activity, the structure of the Gag-Pol substrate, or the molecular interactions of viral structural proteins. Here we report the synthesis and characterization of new cationic N,N-dimethyl[70]fulleropyrrolidinium iodide derivatives that inhibit more than 99% of HIV-1 infectivity at low micromolar concentrations. Analysis of the HIV-1 life cycle indicated that these compounds inhibit viral maturation by impairing Gag and Gag-Pol processing. Importantly, fullerene derivatives 2a-c did not inhibit in vitro PR activity and strongly interacted with HIV immature capsid protein in pull-down experiments...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27999055/unravelling-the-dynamics-of-selection-of-multiresistant-variants-to-integrase-inhibitors-in-an-hiv-1-infected-child-using-ultra-deep-sequencing
#16
Karl Stefic, Maud Salmona, Marisa Capitao, Marion Splittgerber, Zoha Maakaroun-Vermesse, Marie-Laure Néré, Louis Bernard, Marie-Laure Chaix, Francis Barin, Constance Delaugerre
BACKGROUND: Ultra-deep sequencing (UDS) allows detection of minority resistant variants (MRVs) with a threshold of 1% and could be useful to identify variants harbouring single or multiple drug-resistance mutations (DRMs). OBJECTIVES: We analysed the integrase gene region longitudinally using UDS in an HIV-1-infected child rapidly failing a raltegravir-based regimen. METHODS: Longitudinal plasma samples at baseline and weeks 4, 8, 13, 17 and 39 were obtained, as well as the mother's baseline plasma sample...
December 20, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27998286/ultrasensitive-single-genome-sequencing-accurate-targeted-next-generation-sequencing-of-hiv-1-rna
#17
Valerie F Boltz, Jason Rausch, Wei Shao, Junko Hattori, Brian Luke, Frank Maldarelli, John W Mellors, Mary F Kearney, John M Coffin
BACKGROUND: Although next generation sequencing (NGS) offers the potential for studying virus populations in unprecedented depth, PCR error, amplification bias and recombination during library construction have limited its use to population sequencing and measurements of unlinked allele frequencies. Here we report a method, termed ultrasensitive Single-Genome Sequencing (uSGS), for NGS library construction and analysis that eliminates PCR errors and recombinants, and generates single-genome sequences of the same quality as the "gold-standard" of HIV-1 single-genome sequencing assay but with more than 100-fold greater depth...
December 20, 2016: Retrovirology
https://www.readbyqxmd.com/read/27992602/receptor-activation-of-hiv-1-env-leads-to-asymmetric-exposure-of-the-gp41-trimer
#18
Mukta D Khasnis, Konstantine Halkidis, Anshul Bhardwaj, Michael J Root
Structural rearrangements of HIV-1 glycoprotein Env promote viral entry through membrane fusion. Env is a symmetric homotrimer with each protomer composed of surface subunit gp120 and transmembrane subunit gp41. Cellular CD4- and chemokine receptor-binding to gp120 coordinate conformational changes in gp41, first to an extended prehairpin intermediate (PHI) and, ultimately, into a fusogenic trimer-of-hairpins (TOH). HIV-1 fusion inhibitors target gp41 in the PHI and block TOH formation. To characterize structural transformations into and through the PHI, we employed asymmetric Env trimers containing both high and low affinity binding sites for individual fusion inhibitors...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27992544/structural-studies-of-a-rationally-selected-multi-drug-resistant-hiv-1-protease-reveal-synergistic-effect-of-distal-mutations-on-flap-dynamics
#19
Johnson Agniswamy, John M Louis, Julien Roche, Robert W Harrison, Irene T Weber
We report structural analysis of HIV protease variant PRS17 which was rationally selected by machine learning to represent wide classes of highly drug-resistant variants. Crystal structures were solved of PRS17 in the inhibitor-free form and in complex with antiviral inhibitor, darunavir. Despite its 17 mutations, PRS17 has only one mutation (V82S) in the inhibitor/substrate binding cavity, yet exhibits high resistance to all clinical inhibitors. PRS17 has none of the major mutations (I47V, I50V, I54ML, L76V and I84V) associated with darunavir resistance, but has 10,000-fold weaker binding affinity relative to the wild type PR...
2016: PloS One
https://www.readbyqxmd.com/read/27992346/prediction-of-hiv-drug-resistance-by-combining-sequence-and-structural-properties
#20
Zoya Khalid, Osman Ugur Sezerman
Drug resistance is a major obstacle faced by therapist in treating HIV infected patients. The reason behind these phenomena is either protein mutation or the changes in gene expression level that induces resistance to drug treatments. These mutations affect the drug binding activity, hence resulting in failure of treatment. Therefore, it is necessary to conduct resistance testing in order to carry out HIV effective therapy. This study combines both sequence and structural features for predicting HIV resistance by applying SVM and Random Forests classifiers...
December 13, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
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