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https://www.readbyqxmd.com/read/27917706/the-changes-of-positive-selection-within-env-gene-of-hiv-1-b-crf07_bc-and-crf08_bc-from-china-over-time
#1
Tingting Li, Binlian Sun, Yanyan Jiang, Haiyan Zeng, Yanpeng Li, Yan Wang, Rongge Yang
: It is not clear about the possible evolutionary changes of the three predominant strains of HIV-1 in China over the course of the epidemic. Envelope (env) gene of HIV-1 is a good target for this evolutionary pressure for its enriched epitopes. METHODS: We collected 159 full or part of env sequences sampled between 1997 and 2010 from database of China, we calculated the genetic distance, detected the positively selected sites by PAML suite and then compared the number using Fisher's exact test between the early period 1997 to 2003and the late period2004 to 2010...
December 5, 2016: Current HIV Research
https://www.readbyqxmd.com/read/27908751/enhanced-potency-of-bivalent-small-molecule-gp41-inhibitors
#2
Vladimir Sofiyev, Hardeep Kaur, Beth A Snyder, Priscilla A Hogan, Roger G Ptak, Peter Hwang, Miriam Gochin
Low molecular weight peptidomimetic inhibitors with hydrophobic pocket binding properties and moderate fusion inhibitory activity against HIV-1 gp41-mediated cell fusion were elaborated by increasing the available surface area for interacting with the heptad repeat-1 (HR1) coiled coil on gp41. Two types of modifications were tested: 1) increasing the overall hydrophobicity of the molecules with an extension that could interact in the HR1 groove, and 2) forming symmetrical dimers with two peptidomimetic motifs that could potentially interact simultaneously in two hydrophobic pockets on the HR1 trimer...
November 19, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27905530/structural-basis-for-broad-neutralization-of-hiv-1-through-the-molecular-recognition-of-10e8-helical-epitope-at-the-membrane-interface
#3
Edurne Rujas, Jose M M Caaveiro, Angélica Partida-Hanon, Naveed Gulzar, Koldo Morante, Beatriz Apellániz, Miguel García-Porras, Marta Bruix, Kouhei Tsumoto, Jamie K Scott, M Ángeles Jiménez, José L Nieva
The mechanism by which the HIV-1 MPER epitope is recognized by the potent neutralizing antibody 10E8 at membrane interfaces remains poorly understood. To solve this problem, we have optimized a 10E8 peptide epitope and analyzed the structure and binding activities of the antibody in membrane and membrane-like environments. The X-ray crystal structure of the Fab-peptide complex in detergents revealed for the first time that the epitope of 10E8 comprises a continuous helix spanning the gp41 MPER/transmembrane domain junction (MPER-N-TMD; Env residues 671-687)...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27881646/activation-and-inactivation-of-primary-human-immunodeficiency-virus-hiv-1-envelope-glycoprotein-trimers-by-cd4-mimetic-compounds
#4
Navid Madani, Amy M Princiotto, Connie Zhao, Fatemeh Jahanbakhshsefidi, Max Mertens, Alon Herschhorn, Bruno Melillo, Amos B Smith, Joseph Sodroski
: Human immunodeficiency virus (HIV-1) entry into cells is mediated by the viral envelope glycoproteins (Env), a trimer of three gp120 exterior glycoproteins and three gp41 transmembrane glycoproteins. The metastable Env is triggered to undergo entry-related conformational changes when gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell. Small-molecule CD4-mimetic compounds (CD4mc) bind gp120 and act as competitive inhibitors of gp120-CD4 engagement. Some CD4mc have been shown to trigger Env prematurely, initially activating Env function, followed by rapid and irreversible inactivation...
November 23, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27855210/potent-and-broad-inhibition-of-hiv-1-by-a-peptide-from-the-gp41-heptad-repeat-2-domain-conjugated-to-the-cxcr4-amino-terminus
#5
George J Leslie, Jianbin Wang, Max W Richardson, Beth S Haggarty, Kevin L Hua, Jennifer Duong, Anthony J Secreto, Andrea P O Jordon, Josephine Romano, Kritika E Kumar, Joshua J DeClercq, Philip D Gregory, Carl H June, Michael J Root, James L Riley, Michael C Holmes, James A Hoxie
HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-HIV activity could be achieved if a 34 amino acid peptide from HR2 (C34) were brought to the site of virus-cell interactions by conjugation to the amino termini of HIV-1 coreceptors CCR5 or CXCR4...
November 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27852851/identification-of-human-anti-hiv-gp160-monoclonal-antibodies-that-make-effective-immunotoxins
#6
Seth H Pincus, Kejing Song, Grace A Maresh, Dean H Hamer, Dimiter S Dimitrov, Weizao Chen, Mei-Yun Zhang, Victor F Ghetie, Po-Ying Chan-Hui, James E Robinson, Ellen S Vitetta
: The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fc-mediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities...
November 16, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27849170/hiv-1-envelope-mimicry-of-host-enzyme-kynureninase-does-not-disrupt-tryptophan-metabolism
#7
Todd Bradley, Guang Yang, Olga Ilkayeva, T Matt Holl, Ruijun Zhang, Jinsong Zhang, Sampa Santra, Christopher B Fox, Steve G Reed, Robert Parks, Cindy M Bowman, Hilary Bouton-Verville, Laura L Sutherland, Richard M Scearce, Nathan Vandergrift, Thomas B Kepler, M Anthony Moody, Hua-Xin Liao, S Munir Alam, Roger McLendon, Jeffrey I Everitt, Christopher B Newgard, Laurent Verkoczy, Garnett Kelsoe, Barton F Haynes
The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb VHDJH and VLJL knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27827447/molecular-basis-for-epitope-recognition-by-non-neutralizing-anti-gp41-antibody-f240
#8
Neelakshi Gohain, William D Tolbert, Chiara Orlandi, Jonathan Richard, Shilei Ding, Xishan Chen, Daniel A Bonsor, Eric J Sundberg, Wuyuan Lu, Krishanu Ray, Andrés Finzi, George K Lewis, Marzena Pazgier
Antibody-dependent cell-mediated cytotoxicity (ADCC) by non-neutralizing antibodies (nnAbs) specific to the HIV envelope (Env) glycoproteins present at the surface of virus sensitized or infected cells plays a role in the effective adaptive immune response to HIV. Here, we explore the molecular basis for the epitope at the disulfide loop region (DLR) of the principal immunodominant domain of gp41, recognized by the well-known nnAb F240. Our structural studies reveal details of the F240-gp41 interface and describe a structure of DLR that is distinct from known conformations of this region studied in the context of either CD4-unliganded Env trimer or the gp41 peptide in the unbound state...
November 9, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27825868/development-of-a-targeted-anti-her2-scfv-chimeric-peptide-for-gene-delivery-into-her2-positive-breast-cancer-cells
#9
Roya Cheraghi, Mahboobeh Nazari, Mohsen Alipour, Asia Majidi, Saman Hosseinkhani
Chimeric polymers are known as suitable carriers for gene delivery. Certain properties are critical for a polymer to be used as a gene delivery vector. A new polymer was designed for the targeted delivery of genes into breast cancer cell lines, based on MPG peptide. It is composed of different functional domains, including HIV gp41, nuclear localization sequence of SV40 T-antigen, two C-terminus repeats of histone H1, and the scFv of anti-HER2 antibody. The results demonstrated that the vector can effectively condense plasmid DNA into nanoparticles with an average size of 250nm...
November 5, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27824249/identifying-transmission-clusters-with-cluster-picker-and-hiv-trace
#10
Rebecca Rose, Susanna L Lamers, James Jarad Dollar, Mary Grabowski, Emma B Hodcroft, Manon Ragonnet-Cronin, Joel O Wertheim, Andrew D Redd, Danielle German, Oliver Laeyendecker
We compared the behavior of two approaches (Cluster Picker and HIV-TRACE) at varying genetic distances to identify transmission clusters. We used three HIV gp41 sequence data sets originating from the Rakai Community Cohort Study: (1) next-generation sequences (NGS) from nine linked couples; (2) NGS from longitudinal sampling of 14 individuals; and (3) Sanger consensus sequences from a cross-sectional dataset (n=1022) containing 91 epidemiologically linked heterosexual couples. We calculated the optimal genetic distance threshold to separate linked versus unlinked NGS datasets using a receiver operating curve analysis (ROC)...
November 8, 2016: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/27822141/hiv-1-nef-promotes-migration-and-chemokine-synthesis-of-human-basophils-and-mast-cells-through-the-interaction-with-cxcr4
#11
Francesca Wanda Rossi, Nella Prevete, Felice Rivellese, Antonio Lobasso, Filomena Napolitano, Francescopaolo Granata, Carmine Selleri, Amato de Paulis
BACKGROUND: The Nef protein can be detected in plasma of HIV-1-infected patients and plays a role in the pathogenesis of HIV-1. Nef produced during the early stages of infection is fundamental in creating the ideal environment for viral replication, e.g. by reducing the ability of infected cells to induce an immune response. AIM: Based on previous experience showing that both Tat and gp41 of HIV-1 are potent chemotactic factors for basophils and mast cells, and gp120 is a powerful stimulus for the release of histamine and cytokines (IL-4 and IL-13) from basophils, in this study we aimed to verify if the HIV Nef protein can exert some effects on basophils and mast cells purified from healthy volunteers through the interaction with the CXCL12 receptor, CXCR4...
2016: Clinical and Molecular Allergy: CMA
https://www.readbyqxmd.com/read/27802337/characterization-of-humoral-immune-responses-against-capsid-protein-p24-and-transmembrane-glycoprotein-gp41-of-human-immunodeficiency-virus-type-1-in-china
#12
Xiufen Li, Yue Wu, Xuqi Ren, Shuyun Deng, Guifang Hu, Shouyi Yu, Shixing Tang
The objective of this study was to extend our previous research and to further characterize the humoral immune responses against HIV-1 p24, gp41 and the specific peptides carrying the immunodominant epitopes (IDEs) that react with human serum samples from HIV-1-infected individuals in China. We found that the majority (90.45%, 180/199) of the samples did not react with any of the three HIV-1 p24 peptides carrying IDEs, but did react with the recombinant full-length p24, suggesting that these samples tested in China were primarily directed against the conformational epitopes of HIV-1 p24...
2016: PloS One
https://www.readbyqxmd.com/read/27799557/cryo-em-structure-of-a-cd4-bound-open-hiv-1-envelope-trimer-reveals-structural-rearrangements-of-the-gp120-v1v2-loop
#13
Haoqing Wang, Alexander A Cohen, Rachel P Galimidi, Harry B Gristick, Grant J Jensen, Pamela J Bjorkman
The HIV-1 envelope (Env) glycoprotein, a trimer of gp120-gp41 heterodimers, relies on conformational flexibility to function in fusing the viral and host membranes. Fusion is achieved after gp120 binds to CD4, the HIV-1 receptor, and a coreceptor, capturing an open conformational state in which the fusion machinery on gp41 gains access to the target cell membrane. In the well-characterized closed Env conformation, the gp120 V1V2 loops interact at the apex of the Env trimer. Less is known about the structure of the open CD4-bound state, in which the V1V2 loops must rearrange and separate to allow access to the coreceptor binding site...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27795437/a-helical-short-peptide-fusion-inhibitor-with-highly-potent-activities-against-hiv-1-hiv-2-and-simian-immunodeficiency-virus
#14
Shengwen Xiong, Pedro Borrego, Xiaohui Ding, Yuanmei Zhu, Andreia Martins, Huihui Chong, Nuno Taveira, Yuxian He
: HIV-2 has already spread to different regions worldwide and currently about 1-2 million people have been infected, calling for new antiviral agents that are effective on both HIV-1 and HIV-2 isolates. T-20 (Enfuvirtide), a 36-mer peptide derived from the C-terminal heptad repeat region (CHR) of gp41, is the only clinically approved HIV-1 fusion inhibitor, but it easily induces drug-resistance and is not active on HIV-2. In this study, we firstly demonstrated that the M-T hook structure was also a vital strategy to enhance the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27795416/creating-an-artificial-tail-anchor-as-a-novel-strategy-to-enhance-the-potency-of-peptide-based-hiv-fusion-inhibitors
#15
Shan Su, Yun Zhu, Sheng Ye, Qianqian Qi, Shuai Xia, Zhenxuan Ma, Fei Yu, Qian Wang, Rongguang Zhang, Shibo Jiang, Lu Lu
: T20 (enfuvirtide) and other peptides derived from the human immunodeficiency virus type 1 (HIV-1) gp41 C-terminal heptad repeat (CHR) region inhibit HIV fusion by binding to the hydrophobic grooves on the N-terminal heptad repeat (NHR)-trimer and blocking the six-helix bundle (6-HB) formation. Several strategies focusing on the binding grooves of NHR-trimer have been adopted to increase antiviral activity of the CHR-peptides. Here we developed a novel and simple strategy to greatly enhance the potency of the existing peptide-based HIV fusion inhibitors...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27795412/design-and-in-vivo-characterization-of-immunoconjugates-targeting-hiv-gp160
#16
Seth H Pincus, Kejing Song, Grace A Maresh, Anderson Frank, David Worthylake, Hye-Kyung Chung, Patricia Polacino, Dean H Hamer, Cody P Coyne, Michael G Rosenblum, John W Marks, Gang Chen, Deborah Weiss, Victor Ghetie, Ellen S Vitetta, James E Robinson, Shiu-Lok Hu
: The envelope (Env) glycoprotein of HIV is expressed on the surface of productively-infected cells, and can be used as a target for cytotoxic immunoconjugates (ICs), in which cell-killing moieties including toxins, drugs, or radionuclides are chemically or genetically linked to monoclonal antibodies (MAbs) or other targeting ligands. Such ICs could be used to eliminate persistent reservoirs of HIV infection. We have found that MAbs which bind to the external loop of gp41, e.g MAb 7B2, make highly effective ICs, particularly when used in combination with soluble CD4...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27795397/release-of-gp120-restraints-leads-to-an-entry-competent-intermediate-state-of-the-hiv-1-envelope-glycoproteins
#17
Alon Herschhorn, Xiaochu Ma, Christopher Gu, John D Ventura, Luis Castillo-Menendez, Bruno Melillo, Daniel S Terry, Amos B Smith, Scott C Blanchard, James B Munro, Walther Mothes, Andrés Finzi, Joseph Sodroski
: Primary human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimers [(gp120/gp41)3] typically exist in a metastable closed conformation (state 1). Binding the CD4 receptor triggers Env to undergo extensive conformational changes to mediate virus entry. We identified specific gp120 residues that restrain Env in state 1. Alteration of these restraining residues destabilized state 1, allowing Env to populate a functional conformation (state 2) intermediate between state 1 and the full CD4-bound state (state 3)...
October 25, 2016: MBio
https://www.readbyqxmd.com/read/27737697/loss-of-cerebellar-neurons-in-the-progression-of-lentiviral-disease-effects-of-cns-permeant-antiretroviral-therapy
#18
Christian Wächter, Lee E Eiden, Nedye Naumann, Candan Depboylu, Eberhard Weihe
BACKGROUND: The majority of investigations on HIV-associated neurocognitive disorders (HAND) neglect the cerebellum in spite of emerging evidence for its role in higher cognitive functions and dysfunctions in common neurodegenerative diseases. METHODS: We systematically investigated the molecular and cellular responses of the cerebellum as contributors to lentiviral infection-induced neurodegeneration, in the simian immunodeficiency virus (SIV)-infected rhesus macaque model for HIV infection and HAND...
October 14, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27737540/site-specific-polymer-attachment-to-hr2-peptide-fusion-inhibitors-against-hiv-1-decreases-binding-association-rates-and-dissociation-rates-rather-than-binding-affinity
#19
Maarten Danial, Angela Stauffer, Frederik R Wurm, Michael J Root, Harm-Anton Klok
A popular strategy to overcome the limited plasma half-life of peptide heptad repeat 2 (HR2) fusion inhibitors against HIV-1 is through conjugation with biocompatible polymers such as poly(ethylene glycol) (PEG). However, despite improved resistance to proteolysis and reduced renal elimination, covalent attachment of polymers often causes a loss in therapeutic potency. In this study, we investigated the molecular origins of the loss in potency upon conjugation of linear, mid-functional and hyperbranched PEG-like polymers to peptides that inhibit HIV-1 - host cell membrane fusion...
October 13, 2016: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/27731975/lytic-inactivation-of-hiv-1-by-dual-engagement-of-gp120-and-gp41-domains-in-the-virus-env-protein-trimer
#20
Bibek Parajuli, Kriti Acharya, Reina Yu, Brendon Ngo, Adel A Rashad, Cameron F Abrams, Irwin M Chaiken
We recently reported discovery of a recombinant chimera, denoted DAVEI (Dual Acting Virucidal Entry Inhibitor), which is able to selectively cause specific and potent lytic inactivation of both pseudotyped and fully infectious HIV-1 virions. The chimera is composed of the lectin cyanovirin-N (CVN) fused to the 20-residue membrane-proximal external region (MPER) of HIV-1 gp41. Since the Env gp120-binding CVN domain on its own is not lytic, we sought here to determine how the MPER(DAVEI) domain is able to endow the chimera with virolytic activity...
October 12, 2016: Biochemistry
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