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https://www.readbyqxmd.com/read/28912582/evolution-of-gag-and-gp41-in-patients-receiving-ritonavir-boosted-protease-inhibitors
#1
Justen Manasa, Vici Varghese, Sergei L Kosakovsky Pond, Soo-Yon Rhee, Philip L Tzou, W Jeffrey Fessel, Karen S Jang, Elizabeth White, Thorsteinn Rögnvaldsson, David A Katzenstein, Robert W Shafer
Several groups have proposed that genotypic determinants in gag and the gp41 cytoplasmic domain (gp41-CD) reduce protease inhibitor (PI) susceptibility without PI-resistance mutations in protease. However, no gag and gp41-CD mutations definitively responsible for reduced PI susceptibility have been identified in individuals with virological failure (VF) while receiving a boosted PI (PI/r)-containing regimen. To identify gag and gp41 mutations under selective PI pressure, we sequenced gag and/or gp41 in 61 individuals with VF on a PI/r (n = 40) or NNRTI (n = 20) containing regimen...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28878072/high-throughput-protein-engineering-improves-the-antigenicity-and-stability-of-soluble-hiv-1-envelope-glycoprotein-sosip-trimers
#2
Jonathan T Sullivan, Chidananda Sulli, Alberto Nilo, Anila Yasmeen, Gabriel Ozorowski, Rogier W Sanders, Andrew B Ward, P J Klasse, John P Moore, Benjamin J Doranz
Soluble envelope glycoprotein (Env) trimers (SOSIP.664 gp140) are attractive HIV-1 vaccine candidates, with structures that mimic the native membrane-bound Env spike (gp160). Since engineering trimers can be limited by the difficulty of rationally predicting beneficial mutations, here we used a more comprehensive mutagenesis approach with the goal of identifying trimer variants with improved antigenic and stability properties. We created 341 cysteine pairs at predicted points of stabilization throughout gp140, 149 proline residue substitutions at every residue of the gp41 ectodomain, and 362 space-filling residue substitutions at every hydrophobic and aromatic residue in gp140...
September 6, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28845271/a3%C3%A2-genetic-analysis-and-natural-polymorphisms-in-hiv-1-gp41-isolates-from-maputo-mozambique
#3
Nália Ismael, Dulce Bila, Diana Mariani, Adolfo Vubil, Nedio Mabunda, Celina Abreu, Ilesh Jani, Amilcar Tanuri
No abstract text is available yet for this article.
March 2017: Virus Evolution
https://www.readbyqxmd.com/read/28834745/improving-the-immunogenicity-of-native-like-hiv-1-envelope-trimers-by-hyperstabilization
#4
Alba Torrents de la Peña, Jean-Philippe Julien, Steven W de Taeye, Fernando Garces, Miklos Guttman, Gabriel Ozorowski, Laura K Pritchard, Anna-Janina Behrens, Eden P Go, Judith A Burger, Edith E Schermer, Kwinten Sliepen, Thomas J Ketas, Pavel Pugach, Anila Yasmeen, Christopher A Cottrell, Jonathan L Torres, Charlotte D Vavourakis, Marit J van Gils, Celia LaBranche, David C Montefiori, Heather Desaire, Max Crispin, Per Johan Klasse, Kelly K Lee, John P Moore, Andrew B Ward, Ian A Wilson, Rogier W Sanders
The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation...
August 22, 2017: Cell Reports
https://www.readbyqxmd.com/read/28834275/synthesis-biological-evaluation-and-molecular-docking-studies-of-novel-4-arylpyridin-1-4h-yl-benzoic-acid-derivatives-as-anti-hiv-1-agents
#5
Saghi Sepehri, Sepehr Soleymani, Rezvan Zabihollahi, Mohammad R Aghasadeghi, Mehdi Sadat, Lotfollah Saghaie, Afshin Fassihi
The structural similarities between N1 substituted 1,4-dihydropyridines and the known gp41 inhibitors, NB-2 and NB-64, were considered in the current research for the design of some novel anti-HIV-1 agents. A series of novel 4-arylpyridin-1(4H)-yl) benzoic acid derivatives were synthesized and after a comprehensive structural elucidation were screened for in vitro anti-HIV-1 activity. Most of the tested compounds displayed moderate to good inhibitory activity against HIV-1 growth and were evaluated for in vitro cytotoxic activity using XTT assay at the concentration of 100 μM...
August 21, 2017: Chemistry & Biodiversity
https://www.readbyqxmd.com/read/28832407/prevalence-and-clinical-impacts-of-hiv-1-intersubtype-recombinants-in-uganda-revealed-by-a-near-full-genome-population-and-deep-sequencing-approaches
#6
Guinevere Q Lee, David R Bangsberg, Theresa Mo, Chris Lachowski, Chanson J Brumme, Wendy Zhang, Viviane D Lima, Yap Boum, Bosco Bwana Mwebesa, Conrad Muzoora, Iren Andia, Yona Mbalibulha, Annet Kembabazi, Ryan Carroll, Mark J Siedner, Jessica E Haberer, A Rain Mocello, Simone H Kigozi, Peter W Hunt, Jeffrey N Martin, P Richard Harrigan
OBJECTIVES: To estimate prevalence, examine time trends, and test for clinical correlates and outcomes associated with HIV-1 intersubtype recombination under a full-genome sequencing context in a rural community in Mbarara, Uganda, where HIV-1 subtypes A1 and D co-circulate. METHODS: Near-full-genome HIV-1 Sanger sequence data was collected from plasma samples of 504 treatment-naïve individuals, who then received PI or NNRTI-containing regimens and were monitored for up to 7...
August 21, 2017: AIDS
https://www.readbyqxmd.com/read/28811070/evaluation-of-sequence-variability-in-hiv-1-gp41-c-peptide-helix-grafted-proteins
#7
Rachel L Tennyson, Susanne N Walker, Terumasa Ikeda, Reuben S Harris, Brian R McNaughton
Many therapeutically-relevant protein-protein interactions (PPIs) have been reported that feature a helix and helix-binding cleft at the interface. Given this, different approaches to disrupting such PPIs have been developed. While short peptides (<15 amino acids) typically do not fold into a stable helix, researchers have reported chemical approaches to constraining helix structure. However, these approaches rely on laborious, and often expensive, chemical synthesis and purification. Our premise is that protein-based solutions that stabilize a therapeutically-relevant helix offer a number of advantages...
August 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28797705/effects-of-hiv-1-gp41-derived-virucidal-peptides-on-virus-like-lipid-membranes
#8
Pablo Carravilla, Antonio Cruz, Itziar Martin-Ugarte, Itziar R Oar-Arteta, Johanna Torralba, Beatriz Apellaniz, Jesús Pérez-Gil, José Requejo-Isidro, Nerea Huarte, José L Nieva
Membrane fusion induced by the envelope glycoprotein enables the intracellular replication of HIV-1; hence, this process constitutes a major target for antiretroviral compounds. It has been proposed that peptides having propensity to interact with membrane interfaces might exert broad antiviral activity against enveloped viruses. To test this hypothesis, in this contribution we have analyzed the antiviral effects of peptides derived from the membrane-proximal external region and the transmembrane domain of the envelope glycoprotein subunit gp41, which display different degrees of interfacial hydrophobicity...
September 19, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28794027/hiv-dna-adenovirus-multiclade-envelope-vaccine-induces-gp41-antibody-immunodominance-in-rhesus-macaques
#9
Qifeng Han, Wilton B Williams, Kevin O Saunders, Kelly E Seaton, Kevin J Wiehe, Nathan Vandergrift, Tarra Von Holle, Ashley M Trama, Robert J Parks, Kan Luo, Thaddeus C Gurley, Thomas B Kepler, Dawn J Marshall, David C Montefiori, Laura L Sutherland, Munir S Alam, John F Whitesides, Cindy Bowman, Sallie R Permar, Barney S Graham, John R Mascola, Patrick C Seed, Koen K A Van Rompay, Georgia D Tomaras, Michael A Moody, Barton F Haynes
Dominant antibody responses in vaccinees who received the multiclade (A, B and C) envelope (Env) DNA/rAd5 vaccine studied in the HIV-1 vaccine trials network (HVTN) efficacy trial 505 (HVTN 505), targeted Env gp41 and cross-reacted with microbial antigens. In this study, we asked if the DNA/rAd5 vaccine induced a similar antibody response in rhesus macaques (RMs) that are commonly used as an animal model for human HIV-1 infections and for testing candidate HIV-1 vaccines. We also asked if gp41 immunodominance could be avoided by immunization of neonatal RMs during the early stages of microbial colonization...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28790381/selective-cytotoxicity-of-a-novel-immunotoxin-based-on-pulchellin-a-chain-for-cells-expressing-hiv-envelope
#10
Mohammad Sadraeian, Francisco E G Guimarães, Ana P U Araújo, David K Worthylake, Louis Jr LeCour, Seth H Pincus
Immunotoxins (ITs), which consist of antibodies conjugated to toxins, have been proposed as a treatment for cancer and chronic infections. To develop and improve the ITs, different toxins such as ricin, have been used, aiming for higher efficacy against target cells. The toxin pulchellin, isolated from the Abrus pulchellus plant, has similar structure and function as ricin. Here we have compared two plant toxins, recombinant A chains from ricin (RAC) and pulchellin (PAC) toxins, for their ability to kill HIV Env-expressing cells...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28783671/potent-and-broad-hiv-neutralizing-antibodies-in-memory-b-cells-and-plasma
#11
LaTonya D Williams, Gilad Ofek, Sebastian Schätzle, Jonathan R McDaniel, Xiaozhi Lu, Nathan I Nicely, Liming Wu, Caleb S Lougheed, Todd Bradley, Mark K Louder, Krisha McKee, Robert T Bailer, Sijy O'Dell, Ivelin S Georgiev, Michael S Seaman, Robert J Parks, Dawn J Marshall, Kara Anasti, Guang Yang, Xiaoyan Nie, Nancy L Tumba, Kevin Wiehe, Kshitij Wagh, Bette Korber, Thomas B Kepler, S Munir Alam, Lynn Morris, Gift Kamanga, Myron S Cohen, Mattia Bonsignori, Shi-Mao Xia, David C Montefiori, Garnett Kelsoe, Feng Gao, John R Mascola, M Anthony Moody, Kevin O Saunders, Hua-Xin Liao, Georgia D Tomaras, George Georgiou, Barton F Haynes
Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1-specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1-infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage...
January 27, 2017: Science Immunology
https://www.readbyqxmd.com/read/28757252/non-neutralizing-antibodies-alter-the-course-of-hiv-1-infection-in%C3%A2-vivo
#12
Joshua A Horwitz, Yotam Bar-On, Ching-Lan Lu, Daniela Fera, Ainsley A K Lockhart, Julio C C Lorenzi, Lilian Nogueira, Jovana Golijanin, Johannes F Scheid, Michael S Seaman, Anna Gazumyan, Susan Zolla-Pazner, Michel C Nussenzweig
Non-neutralizing antibodies (nnAbs) to HIV-1 show little measurable activity in prevention or therapy in animal models yet were the only correlate of protection in the RV144 vaccine trial. To investigate the role of nnAbs on HIV-1 infection in vivo, we devised a replication-competent HIV-1 reporter virus that expresses a heterologous HA-tag on the surface of infected cells and virions. Anti-HA antibodies bind to, but do not neutralize, the reporter virus in vitro. However, anti-HA protects against infection in humanized mice and strongly selects for nnAb-resistant viruses in an entirely Fc-dependent manner...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28747507/roles-of-cellular-nsf-protein-in-entry-and-nuclear-egress-of-budded-virions-of-autographa-californica-multiple-nucleopolyhedrovirus
#13
Ya Guo, Qi Yue, Jinli Gao, Zhe Wang, Yun-Ru Chen, Gary W Blissard, Tong-Xian Liu, Zhaofei Li
In eukaryotic cells, the soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) proteins comprise the minimal machinery that triggers fusion of transport vesicles with their target membranes. Comparative studies revealed that genes encoding the components of the SNARE system are highly conserved in yeast, insect, and human genomes. Upon infection of insect cells by the virus AcMNPV, the transcript levels of most SNARE genes were initially up-regulated. We found that overexpression of dominant-negative (DN) forms of NSF or knock-down of the expression of NSF, the key regulator of the SNARE system, significantly affected the infectious AcMNPV production...
July 26, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28743743/characterization-of-a-stable-hiv-1-b-c-recombinant-soluble-and-trimeric-envelope-glycoprotein-env-highly-resistant-to-cd4-induced-conformational-changes
#14
Rajesh Kumar, Gabriel Ozorowski, Vivek Kumar, Lauren G Holden, Tripti Shrivastava, Shilpa Patil, Suprit Deshpande, Andrew B Ward, Jayanta Bhattacharya
The HIV-1 envelope (Env) is a glycoprotein which is a trimer of heterodimer containing gp120 and gp41 subunits, mediates virus entry and is a major target of broadly neutralizing antibodies (bnAbs) developed during infection in some individuals. The engagement of the HIV-1 gp120 glycoprotein to the host CD4 protein triggers conformational changes in gp120 that allows its binding to coreceptors, and is necessary for virus entry to establish infection. Native-like HIV-1 Env immunogens representing distinct clades have been proposed to improve immunogenicity of bnAbs...
July 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28740221/escape-from-humoral-immunity-is-associated-with-treatment-failure-in-hiv-1-infected-patients-receiving-long-term-antiretroviral-therapy
#15
Yabo Ouyang, Qianqian Yin, Wei Li, Zhenpeng Li, Desheng Kong, Yanling Wu, Kunxue Hong, Hui Xing, Yiming Shao, Shibo Jiang, Tianlei Ying, Liying Ma
Interindividual heterogeneity in the disease progression of HIV-1-infected patients receiving long-term antiretroviral therapy suggests that some host-related factors may have limited treatment efficacy. To understand the nature of factors contributing to treatment failure, we performed a retrospective cohort study of 45 chronically HIV-1-infected individuals sharing a similar demographics and route of infection, compared the differences between virologically suppressed (VS) and treatment failure (TF) patients with respect to clinical, immunological and virological characteristics...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28727817/immunogenicity-of-a-novel-clade-b-hiv-1-vaccine-combination-results-of-phase-1-randomized-placebo-controlled-trial-of-an-hiv-1-gm-csf-expressing-dna-prime-with-a-modified-vaccinia-ankara-vaccine-boost-in-healthy-hiv-1-uninfected-adults
#16
Susan P Buchbinder, Nicole A Grunenberg, Brittany J Sanchez, Kelly E Seaton, Guido Ferrari, M Anthony Moody, Nicole Frahm, David C Montefiori, Christine M Hay, Paul A Goepfert, Lindsey R Baden, Harriet L Robinson, Xuesong Yu, Peter B Gilbert, M Juliana McElrath, Yunda Huang, Georgia D Tomaras
BACKGROUND: A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. METHODS: Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively...
2017: PloS One
https://www.readbyqxmd.com/read/28713388/exploiting-natural-cross-reactivity-between-human-immunodeficiency-virus-hiv-1-p17-protein-and-anti-gp41-2f5-antibody-to-induce-hiv-1-neutralizing-responses-in-vivo
#17
Bernard Verrier, Stéphane Paul, Céline Terrat, Liza Bastide, Agathe Ensinas, Capucine Phelip, Blandine Chanut, Laura Bulens-Grassigny, Fabienne Jospin, Christophe Guillon
Anti-p17 antibodies are able to neutralize human immunodeficiency virus (HIV) entry in a mouse model. In this study, we identified a region of sequence similarity between the epitopes of anti-p17 neutralizing antibodies and anti-gp41 neutralizing 2F5 antibody and verified cross-reactivity between p17 and 2F5 in vitro. The p17 sequence was modified to increase sequence identity between the p17 and 2F5 epitopes, which resulted in enhanced cross-reactivity in vitro. Immunogenicity of wild-type and modified p17 was characterized in a rabbit model...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28712768/neutralizing-antibodies-against-a-specific-human-immunodeficiency-virus-gp41-epitope-are-associated-with-long-term-non-progressor-status
#18
Olivier Lucar, Bin Su, Valérie Potard, Assia Samri, Brigitte Autran, Christiane Moog, Patrice Debré, Vincent Vieillard
Antibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4(+) T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long-term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with <5% (5/104) of HIV-1 progressor patients...
August 2017: EBioMedicine
https://www.readbyqxmd.com/read/28700571/open-and-closed-structures-reveal-allostery-and-pliability-in-the-hiv-1-envelope-spike
#19
Gabriel Ozorowski, Jesper Pallesen, Natalia de Val, Dmitry Lyumkis, Christopher A Cottrell, Jonathan L Torres, Jeffrey Copps, Robyn L Stanfield, Albert Cupo, Pavel Pugach, John P Moore, Ian A Wilson, Andrew B Ward
For many enveloped viruses, binding to a receptor(s) on a host cell acts as the first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion. Although Env can tolerate a high degree of mutation in five variable regions (V1-V5), and also at N-linked glycosylation sites that contribute roughly half the mass of Env, the functional sites for recognition of receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral fitness...
July 20, 2017: Nature
https://www.readbyqxmd.com/read/28696158/immunization-with-hiv-1-envelope-t20-encoding-dna-vaccines-elicits-cross-clade-neutralizing-antibody-responses
#20
S Stenler, K E Lundin, L Hansen, S Petkov, N Mozafari, M Isaguliants, P Blomberg, C I E Smith, D M Goldenberg, C-H Chang, K Ljungberg, J Hinkula, B Wahren
BACKGROUND: Genetic immunization is expected to induce the expression of antigens in a native form. The encoded peptide epitopes are presented on endogenous MHC molecules, mimicking antigen presentation during a viral infection. We have explored the potential of enfuvirtide (T20), a short HIV peptide with antiviral properties, to enhance immune response to HIV antigens. To generate an expression vector, the T20 sequence was cloned into a conventional plasmid, the novel minicircle construct, and a replicon plasmid...
July 11, 2017: Human Vaccines & Immunotherapeutics
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