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https://www.readbyqxmd.com/read/28448574/fusion-expression-of-occludin-extracellular-loops-and-an-%C3%AE-helical-bundle-a-new-research-model-for-tight-junction
#1
Xiaojing Chi, Xia Zhao, Wei Wang, Yuqiang Niu, Min Cheng, Xiuying Liu, Sheng Cui, Wei Yang
Tight junctions (TJs) are the outermost structures of intercellular junctions and are highly specialized membrane domains involved in many important cellular processes. However, most TJ proteins are four-time transmembrane proteins and are difficult to express in their correct soluble form, which limits their functional study and therapeutic application. Human occludin (OCLN) is a major component of TJs and an essential co-receptor for hepatitis C virus (HCV) cell entry. To explore expression strategy for recombinant TJ proteins possessing integrated and functional extracellular loops, OCLN was here used as a model molecule, and several prokaryotic fusion constructs were designed by docking OCLN extracellular loops (ECLs) to HIV-1 gp41 NHR and CHR six-helical bundle (6HV1); then their biophysical features and anti-HCV activity were evaluated...
2017: PloS One
https://www.readbyqxmd.com/read/28422789/antigp41-membrane-proximal-external-region-antibodies-and-the-art-of-using-the-membrane-for-neutralization
#2
Nichole Cerutti, Juan Luis Loredo-Varela, Christophe Caillat, Winfried Weissenhorn
PURPOSE OF REVIEW: We summarize the latest research on the progress to understand the neutralizing epitopes present within the membrane proximal external region (MPER) of the HIV-1 fusion protein subunit gp41. RECENT FINDINGS: The HIV-1 fusion protein subunit gp41 contains a highly conserved sequence that is essential for membrane fusion and targeted by broadly neutralizing antibodies such as 2F5, 4E10, Z13e1, and 10E8. These antibodies recognize a linear gp41 epitope with high affinity, but require additional hydrophobic sequences present in their heavy chain CDR3 for neutralization...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28402882/gating-charge-calculations-by-computational-electrophysiology-simulations
#3
Jan-Philipp Machtens, Rodolfo Briones, Claudia Alleva, Bert L de Groot, Christoph Fahlke
Electrical cell signaling requires adjustment of ion channel, receptor, or transporter function in response to changes in membrane potential. For the majority of such membrane proteins, the molecular details of voltage sensing remain insufficiently understood. Here, we present a molecular dynamics simulation-based method to determine the underlying charge movement across the membrane-the gating charge-by measuring electrical capacitor properties of membrane-embedded proteins. We illustrate the approach by calculating the charge transfer upon membrane insertion of the HIV gp41 fusion peptide, and validate the method on two prototypical voltage-dependent proteins, the Kv1...
April 11, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28396421/antigenicity-defined-conformations-of-an-extremely-neutralization-resistant-hiv-1-envelope-spike
#4
Yongfei Cai, Selen Karaca-Griffin, Jia Chen, Sai Tian, Nicholas Fredette, Christine E Linton, Sophia Rits-Volloch, Jianming Lu, Kshitij Wagh, James Theiler, Bette Korber, Michael S Seaman, Stephen C Harrison, Andrea Carfi, Bing Chen
The extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160)3, cleaved to (gp120/gp41)3] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easy-to-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
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
#5
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/28390972/targeting-cell-surface-hiv-1-env-protein-to-suppress-infectious-virus-formation
#6
Arangassery Rosemary Bastian, Charles G Ang, Kantharaju Kamanna, Farida Shaheen, Yu-Hung Huang, Karyn McFadden, Caitlin Duffy, Lauren D Bailey, Ramalingam Venkat Kalyana Sundaram, Irwin Chaiken
HIV-1 Env protein is essential for host cell entry, and targeting Env remains an important antiretroviral strategy. We previously found that a peptide triazole thiol KR13 and its gold nanoparticle conjugate AuNP-KR13 directly and irreversibly inactivate the virus by targeting the Env protein, leading to virus gp120 shedding, membrane disruption and p24 capsid protein release. Here, we examined the consequences of targeting cell-surface Env with the virus inactivators. We found that both agents led to formation of non-infectious virus from transiently transfected HEK293T cells...
April 6, 2017: Virus Research
https://www.readbyqxmd.com/read/28386076/quantitative-humoral-profiling-of-the-hiv-1-proteome-in-elite-controllers-and-patients-with-very-long-term-efficient-antiretroviral-therapy
#7
Wang Zhang, Mohammed M Morshed, Kajsa Noyan, Aman Russom, Anders Sönnerborg, Ujjwal Neogi
A major challenge in evaluating the success of HIV eradication approaches is the need for accurate measurement of persistent HIV during effective antiretroviral therapy (ART). Previous studies have reported that the anti-HIV antibody assay "luciferase immuno-precipitation systems (LIPS)" can distinguish HIV-infected individuals harboring different sizes of the viral reservoirs. We performed antibody profiling of HIV-1 proteomes using LIPS in viremic progressors (n = 38), elite controllers (ECs; n = 19) and patients with fully suppressive long-term antiretroviral therapy (ART) (n = 19) (mean 17 years)...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28381572/improving-the-expression-and-purification-of-soluble-recombinant-native-like-hiv-1-envelope-glycoprotein-trimers-by-targeted-sequence-changes
#8
Rajesh P Ringe, Gabriel Ozorowski, Anila Yasmeen, Albert Cupo, Victor M Cruz Portillo, Pavel Pugach, Michael Golabek, Kimmo Rantalainen, Lauren G Holden, Christopher A Cottrell, Ian A Wilson, Rogier W Sanders, Andrew B Ward, P J Klasse, John P Moore
Soluble, recombinant native-like envelope glycoprotein (Env) trimers of various human immunodeficiency virus type 1 (HIV-1) genotypes are being developed for structural studies and as vaccine candidates aimed at the induction of broadly neutralizing antibodies (bNAbs). The prototypic design is designated SOSIP.664, but many HIV-1 env genes do not yield fully native-like trimers efficiently. One such env gene is CZA97.012 from a neutralization-resistant (Tier-2) clade C virus. As appropriately purified, native-like CZA97...
April 5, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28375134/report-antibacterial-activity-of-a-peptide-derived-from-hiv-1-mn-strain-gp41-envelope-glycoprotein-against-methicillin-resistant-staphylococcus-aureus
#9
Sin-Yeang Teow, Syed Atif Ali
Peptides derived from HIV-1 transmembrane proteins have been extensively studied for antimicrobial activities, and they are known as antimicrobial peptides (AMPs). These AMPs have also been reported to potently combat the drug-resistant microbes. In this study, we demonstrated that peptide #6383 originated from HIV-1 MN strain membrane-spanning domain of gp41 was active (2-log reductions) at 100βg/mL (56.5βM) against methicillin-resistant Staphylococcus aureus (MRSA) in 10% and 50% human plasma-supplemented phosphate buffered saline (PBS)...
November 2016: Pakistan Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28356533/a-lipopeptide-hiv-1-2-fusion-inhibitor-with-highly-potent-in-vitro-ex-vivo-and-in-vivo-antiviral-activity
#10
Huihui Chong, Jing Xue, Shengwen Xiong, Zhe Cong, Xiaohui Ding, Yuanmei Zhu, Zixuan Liu, Ting Chen, Yifan Feng, Lei He, Yan Guo, Qiang Wei, Yusen Zhou, Chuan Qin, Yuxian He
Peptides derived from the C-terminal heptad repeat (CHR) region of the HIV-1 fusogenic protein gp41 are potent viral entry inhibitors, and currently enfuvirtide (T-20) is the only one for clinical use; however, emerging drug-resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, HIV-2 sequence, intra-helical salt-bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad and long-lasting antiviral activity...
March 29, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28340570/the-therapeutic-hiv-env-c5-gp41-vaccine-candidate-vacc-c5-induces-specific-t-cell-regulation-in-a-phase-i-ii-clinical-study
#11
Kristin Brekke, Maja Sommerfelt, Mats Ökvist, Anne Margarita Dyrhol-Riise, Dag Kvale
BACKGROUND: Levels of non-neutralising antibodies (AB) to the C5 domain of HIV Env gp120 are inversely related to progression of HIV infection. In this phase I/II clinical study we investigated safety of Vacc-C5, a peptide-based therapeutic vaccine candidate corresponding to C5/gp41(732-744) as well as the effects on pre-existing AB levels to C5/gp41(732-744), immune activation and T cell responses including exploratory assessments of Vacc-C5-induced T cell regulation. Our hypothesis was that exposure of the C5 peptide motif may have detrimental effects due to several of its HLA-like features and that enhancement of non-neutralising anti-C5 AB by vaccination could reduce C5 exposure and thereby chronic immune activation...
March 24, 2017: BMC Infectious Diseases
https://www.readbyqxmd.com/read/28300601/functional-contacts-between-mper-and-the-anti-hiv-1-broadly-neutralizing-antibody-4e10-extend-into-the-core-of-the-membrane
#12
Edurne Rujas, Sara Insausti, Miguel García-Porras, Rubén Sánchez-Eugenia, Kouhei Tsumoto, José L Nieva, Jose M M Caaveiro
The exceptional breadth of broadly neutralizing antibodies (bNAbs) against the membrane-proximal external region (MPER) of the transmembrane protein gp41 makes this class of antibodies an ideal model to design HIV vaccines. From a practical point of view, however, the preparation of vaccines eliciting bNAbs is still a major roadblock that limits their clinical application. Fresh mechanistic insights are necessary to develop more effective strategies. In particular, the function of the unusually long complementarity-determining region three of the heavy chain (CDRH3) of 4E10, an anti-MPER bNAb, is an open question that fascinates researchers in the field...
April 21, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28282446/antigenic-and-immunosuppressive-properties-of-a-trimeric-recombinant-transmembrane-envelope-protein-gp41-of-hiv-1
#13
Michael Mühle, Melissa Lehmann, Kerstin Hoffmann, Daniel Stern, Tobias Kroniger, Werner Luttmann, Joachim Denner
The transmembrane envelope (TM) protein gp41 of the human immunodeficiency virus-1 (HIV-1) plays an important role during virus infection inducing the fusion of the viral and cellular membranes. In addition, there are indications that the TM protein plays a role in the immunopathogenesis leading to the acquired immunodeficiency syndrome (AIDS). Inactivated virus particles and recombinant gp41 have been reported to inhibit lymphocyte proliferation, as well as to alter cytokine release and gene expression. The same was shown for a peptide corresponding to a highly conserved domain of all retroviral TM proteins, the immunosuppressive domain...
2017: PloS One
https://www.readbyqxmd.com/read/28250125/conformational-states-of-a-soluble-uncleaved-hiv-1-envelope-trimer
#14
Yuhang Liu, Junhua Pan, Yongfei Cai, Nikolaus Grigorieff, Stephen C Harrison, Bing Chen
HIV-1 envelope spike [Env; trimeric (gp160)3, cleaved to (gp120/gp41)3] induces membrane fusion, leading to viral entry. It is also the viral component targeted by neutralizing antibodies. Vaccine development requires production, in quantities suitable for clinical studies, of a recombinant form that resembles functional Env. HIV-1 gp140 trimers - the uncleaved ectodomains of (gp160)3 - from a few selected viral isolates adopt a compact conformation with many antigenic properties of native Env spikes. One is currently being evaluated in a clinical trial...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28250119/new-connections-cell-to-cell-hiv-1-transmission-resistance-to-broadly-neutralizing-antibodies-and-an-envelope-sorting-motif
#15
S Abigail Smith, Cynthia A Derdeyn
HIV-1 infection from cell to cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al show that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell to cell infection in a context dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28237764/evaluation-of-a-novel-multi-immunogen-vaccine-strategy-for-targeting-4e10-10e8-neutralizing-epitopes-on-hiv-1-gp41-membrane-proximal-external-region
#16
Saikat Banerjee, Heliang Shi, Marisa Banasik, Hojin Moon, William Lees, Yali Qin, Andrew Harley, Adrian Shepherd, Michael W Cho
The membrane proximal external region (MPER) of HIV-1 gp41 is targeted by broadly neutralizing antibodies (bnAbs) 4E10 and 10E8. In this proof-of-concept study, we evaluated a novel multi-immunogen vaccine strategy referred to as Incremental, Phased Antigenic Stimulation for Rapid Antibody Maturation (IPAS-RAM) to induce 4E10/10E8-like bnAbs. Rabbits were immunized sequentially, but in a phased manner, with three immunogens that are progressively more native (gp41-28×3, gp41-54CT, and rVV-gp160DH12). Although nAbs were not induced, epitope-mapping analyses indicated that IPAS-RAM vaccination was better able to target antibodies towards the 4E10/10E8 epitopes than homologous prime-boost immunization using gp41-28×3 alone...
May 2017: Virology
https://www.readbyqxmd.com/read/28225819/lipid-interactions-and-angle-of-approach-to-the-hiv-1-viral-membrane-of-broadly-neutralizing-antibody-10e8-insights-for-vaccine-and-therapeutic-design
#17
Adriana Irimia, Andreia M Serra, Anita Sarkar, Ronald Jacak, Oleksandr Kalyuzhniy, Devin Sok, Karen L Saye-Francisco, Torben Schiffner, Ryan Tingle, Michael Kubitz, Yumiko Adachi, Robyn L Stanfield, Marc C Deller, Dennis R Burton, William R Schief, Ian A Wilson
Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the envelope (Env) viral glycoprotein and is a major vaccine target. However, the MPER is proximal to the viral membrane and may be laterally inserted into the membrane in the Env prefusion form. Nevertheless, 10E8 has not been reported to have significant lipid-binding reactivity...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28209172/evaluation-of-the-contribution-of-the-transmembrane-region-to-the-ectodomain-conformation-of-the-human-immunodeficiency-virus-hiv-1-envelope-glycoprotein
#18
Hanh T Nguyen, Navid Madani, Haitao Ding, Emerald Elder, Amy Princiotto, Christopher Gu, Patrice Darby, James Alin, Alon Herschhorn, John C Kappes, Youdong Mao, Joseph G Sodroski
BACKGROUND: The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env), a Type 1 transmembrane protein, assembles into a trimeric spike complex that mediates virus entry into host cells. The high potential energy of the metastable, unliganded Env trimer is maintained by multiple non-covalent contacts among the gp120 exterior and gp41 transmembrane Env subunits. Structural studies suggest that the gp41 transmembrane region forms a left-handed coiled coil that contributes to the Env trimer interprotomer contacts...
February 16, 2017: Virology Journal
https://www.readbyqxmd.com/read/28207485/antigp41-membrane-proximal-external-region-antibodies-and-the-art-of-using-the-membrane-for-neutralization
#19
Nichole Cerutti, Juan Luis Loredo-Varela, Christophe Caillat, Winfried Weissenhorn
PURPOSE OF REVIEW: We summarize the latest research on the progress to understand the neutralizing epitopes present within the membrane proximal external region (MPER) of the HIV-1 fusion protein subunit gp41. RECENT FINDINGS: The HIV-1 fusion protein subunit gp41 contains a highly conserved sequence that is essential for membrane fusion and targeted by broadly neutralizing antibodies such as 2F5, 4E10, Z13e1, and 10E8. These antibodies recognize a linear gp41 epitope with high affinity, but require additional hydrophobic sequences present in their heavy chain CDR3 for neutralization...
February 15, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28203239/sublingual-priming-with-a-hiv-gp41-based-subunit-vaccine-elicits-mucosal-antibodies-and-persistent-b-memory-responses-in-non-human-primates
#20
Selma Bekri, Pierre Bourdely, Carmelo Luci, Nathalie Dereuddre-Bosquet, Bin Su, Frédéric Martinon, Véronique M Braud, Irene Luque, Pedro L Mateo, Sara Crespillo, Francisco Conejero-Lara, Christiane Moog, Roger Le Grand, Fabienne Anjuère
Persistent B cell responses in mucosal tissues are crucial to control infection against sexually transmitted pathogens like human immunodeficiency virus 1 (HIV-1). The genital tract is a major site of infection by HIV. Sublingual (SL) immunization in mice was previously shown to generate HIV-specific B cell immunity that disseminates to the genital tract. We report here the immunogenicity in female cynomolgus macaques of a SL vaccine based on a modified gp41 polypeptide coupled to the cholera toxin B subunit designed to expose hidden epitopes and to improve mucosal retention...
2017: Frontiers in Immunology
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