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Hiv and broadly neutralizing antibody

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https://www.readbyqxmd.com/read/27919754/neutralization-takes-precedence-over-igg-or-iga-isotype-related-functions-in-mucosal-hiv-1-antibody-mediated-protection
#1
Rena D Astronomo, Sampa Santra, Lamar Ballweber-Fleming, Katharine G Westerberg, Linh Mach, Tiffany Hensley-McBain, Laura Sutherland, Benjamin Mildenberg, Georgeanna Morton, Nicole L Yates, Gregory J Mize, Justin Pollara, Florian Hladik, Christina Ochsenbauer, Thomas N Denny, Ranjit Warrier, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Jaranit Kaewkungwal, Guido Ferrari, George M Shaw, Shi-Mao Xia, Hua-Xin Liao, David C Montefiori, Georgia D Tomaras, Barton F Haynes, M Juliana McElrath
HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching...
November 21, 2016: EBioMedicine
https://www.readbyqxmd.com/read/27908641/free-energy-perturbation-calculation-of-relative-binding-free-energy-between-broadly-neutralizing-antibodies-and-the-gp120-glycoprotein-of-hiv-1
#2
Anthony J Clark, Tatyana Gindin, Baoshan Zhang, Lingle Wang, Robert Abel, Colleen S Murret, Fang Xu, Amy Bao, Nina J Lu, Tongqing Zhou, Peter D Kwong, Lawrence Shapiro, Barry Honig, Richard A Friesner
Direct calculation of relative binding affinities between antibodies and antigens is a long-sought goal. However, despite substantial efforts, no generally applicable computational method has been described. Here we describe a systematic free energy perturbation (FEP) protocol and calculate the binding affinities between the gp120 envelope glycoprotein of HIV-1 and three broadly neutralizing antibodies (bNAbs) of the VRC01 class. The protocol has been adapted from successful studies of small molecules to address the challenges associated with modeling protein-protein interactions...
November 28, 2016: Journal of Molecular Biology
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/27894306/first-phase-i-human-clinical-trial-of-a-killed-whole-hiv-1-vaccine-demonstration-of-its-safety-and-enhancement-of-anti-hiv-antibody-responses
#4
Eunsil Choi, Chad J Michalski, Seung Ho Choo, Gyoung Nyoun Kim, Elizabeth Banasikowska, Sangkyun Lee, Kunyu Wu, Hwa-Yong An, Anthony Mills, Stefan Schneider, U Fritz Bredeek, Daniel R Coulston, Shilei Ding, Andrés Finzi, Meijuan Tian, Katja Klein, Eric J Arts, Jamie F S Mann, Yong Gao, C Yong Kang
BACKGROUND: Vaccination with inactivated (killed) whole-virus particles has been used to prevent a wide range of viral diseases. However, for an HIV vaccine this approach has been largely negated due to inherent safety concerns, despite the ability of killed whole-virus vaccines to generate a strong, predominantly antibody-mediated immune response in vivo. HIV-1 Clade B NL4-3 was genetically modified by deleting the nef and vpu genes and substituting the coding sequence for the Env signal peptide with that of honeybee melittin signal peptide to produce a less virulent and more replication efficient virus...
November 28, 2016: Retrovirology
https://www.readbyqxmd.com/read/27891132/impact-of-chronic-hiv-siv-infection-on-t-follicular-helper-cell-subsets-and-germinal-center-homeostasis
#5
REVIEW
Stéphanie Graff-Dubois, Angeline Rouers, Arnaud Moris
The discovery of broad and potent HIV-1 neutralizing antibodies (bNAbs) has renewed optimism for developing an effective vaccine against HIV-1. The generation of most bNAbs requires multiple rounds of B cell receptor affinity maturation, suggesting a crucial role of follicular helper T (Tfh) cells in their production. However, less than 1% of HIV-infected patients develop bNAbs that arise late in the course of infection, indicating probable Tfh and B cell dysfunctions in this context. Since the last few years, many studies have characterized Tfh cells from lymph nodes and spleen of HIV-infected individuals and SIV-infected macaques...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27889424/hiv-vaccines-one-step-closer
#6
Michael Sze Yuan Low, David Tarlinton
Currently there is no effective vaccine against human immunodeficiency virus (HIV). Four recently published studies in Cell and Immunity now show that using planned sequential boosting with antigens to guide the humoral response towards broadly neutralizing antibodies could provide a solution to achieving vaccination against HIV-1.
November 23, 2016: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/27879316/structure-based-design-of-cyclically-permuted-hiv-1-gp120-trimers-that-elicit-neutralizing-antibodies
#7
Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G Joyce, Somnath Dutta, Celia C LaBranche, David C Montefiori, Jessica A Flynn, Raghavan Varadarajan
A major goal for HIV-1 vaccine development is an ability to elicit strong and durable broadly neutralizing antibody (bNAb) responses. The trimeric envelope glycoprotein (Env) spikes on HIV-1 are known to contain multiple epitopes that are susceptible to bNAbs isolated from infected individuals. Nonetheless, all trimeric and monomeric Env immunogens designed to date have failed to elicit such antibodies. We report the structure guided design of HIV-1 cyclically permuted gp120 that forms homogeneous, stable trimers and displays enhanced binding to multiple bNAbs, including VRC01, VRC03, VRC-PG04, PGT128 and the quaternary epitope-specific bNAbs PGT145 and PGDM1400...
November 22, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27871328/membrane-bound-modified-form-of-clade-b-env-jrcsf-is-suitable-for-immunogen-design-as-it-is-efficiently-cleaved-and-displays-all-the-broadly-neutralizing-epitopes-including-v2-and-c2-domain-dependent-conformational-epitopes
#8
Supratik Das, Saikat Boliar, Nivedita Mitra, Sweety Samal, Manish Bansal, Wayne C Koff, Bimal K Chakrabarti
BACKGROUND: Antigenicity of HIV-1 envelope proteins (Envs) of both lab-adapted and primary isolates expressed on the cell surface rarely match with in vitro neutralization of viruses, pseudo-typed with corresponding Envs. Often, both neutralizing and non-neutralizing antibodies bind to Envs expressed on the cell membrane. This could be due to the lack of efficient cleavage of Env expressed on the cell surface. Naturally occurring, efficiently cleaved Envs with appropriate antigenic properties are relatively rare...
November 21, 2016: Retrovirology
https://www.readbyqxmd.com/read/27869733/antiviral-therapy-by-hiv-1-broadly-neutralizing-and-inhibitory-antibodies
#9
REVIEW
Zhiqing Zhang, Shaowei Li, Ying Gu, Ningshao Xia
Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immune deficiency syndrome (AIDS), a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART) but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1...
November 18, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27853288/enhancing-virion-tethering-by-bst2-sensitizes-productively-and-latently-hiv-infected-t-cells-to-adcc-mediated-by-broadly-neutralizing-antibodies
#10
Tram N Q Pham, Sabelo Lukhele, Frédéric Dallaire, Gabrielle Perron, Éric A Cohen
Binding of anti-HIV antibodies (Abs) to envelope (Env) glycoproteins on infected cells can mark them for elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). BST2, a type I interferon (IFN)-stimulated restriction factor that anchors nascent Env-containing virions at the surface of infected cells has been shown to enhance ADCC functions. In a comprehensive analysis of ADCC potency by neutralizing anti-HIV Abs (NAbs), we show in this study that NAbs are capable of mediating ADCC against HIV-infected T cells with 3BNC117, PGT126 and PG9 being most efficient...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27851923/hiv-broadly-neutralizing-antibodies-taking-good-care-of-the-98
#11
Devin Sok, Dennis R Burton
In this issue of Immunity, Huang et al. (2016) describe an exceptionally broad and potent neutralizing antibody to HIV. This antibody, N6, is capable of neutralizing up to 98% of global isolates with a potent median IC50 of 0.04 μg/mL, making it the current "best-in-class" for bNAbs targeting the CD4 binding site.
November 15, 2016: Immunity
https://www.readbyqxmd.com/read/27851912/identification-of-a-cd4-binding-site-antibody-to-hiv-that-evolved-near-pan-neutralization-breadth
#12
Jinghe Huang, Byong H Kang, Elise Ishida, Tongqing Zhou, Trevor Griesman, Zizhang Sheng, Fan Wu, Nicole A Doria-Rose, Baoshan Zhang, Krisha McKee, Sijy O'Dell, Gwo-Yu Chuang, Aliaksandr Druz, Ivelin S Georgiev, Chaim A Schramm, Anqi Zheng, M Gordon Joyce, Mangaiarkarasi Asokan, Amy Ransier, Sam Darko, Stephen A Migueles, Robert T Bailer, Mark K Louder, S Munir Alam, Robert Parks, Garnett Kelsoe, Tarra Von Holle, Barton F Haynes, Daniel C Douek, Vanessa Hirsch, Michael S Seaman, Lawrence Shapiro, John R Mascola, Peter D Kwong, Mark Connors
Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain...
November 15, 2016: Immunity
https://www.readbyqxmd.com/read/27846415/chinks-in-the-armor-of-the-hiv-1-envelope-glycan-shield-implications-for-immune-escape-from-anti-glycan-broadly-neutralizing-antibodies
#13
Thandeka Moyo, Roux-Cil Ferreira, Reyaaz Davids, Zarinah Sonday, Penny L Moore, Simon A Travers, Natasha T Wood, Jeffrey R Dorfman
Glycans on HIV-1 Envelope serve multiple functions including blocking epitopes from antibodies. We show that removal of glycan 301, a major target of anti-V3/glycan antibodies, has substantially different effects in two viruses. While glycan 301 on Du156.12 blocks epitopes commonly recognized by sera from chronically HIV-1-infected individuals, it does not do so on CAP45.G3, suggesting that removing the 301 glycan has a smaller effect on the integrity of the glycan shield in CAP45.G3. Changes in sensitivity to broadly neutralizing monoclonal antibodies suggest that the interaction between glycan 301 and the CD4 binding site differ substantially between these 2 viruses...
November 12, 2016: Virology
https://www.readbyqxmd.com/read/27835755/expression-of-hiv-1-broadly-neutralizing-antibodies-mediated-by-recombinant-adeno-associated-virus-8-in-vitro-and-in-vivo
#14
Yongjiao Yu, Lu Fu, Xiaoyu Jiang, Shanshan Guan, Ziyu Kuai, Wei Kong, Yuhua Shi, Yaming Shan
Despite unremitting efforts since the discovery of human immunodeficiency virus type 1 (HIV-1), an effective vaccine has not been generated. Viral vector-mediated transfer for expression of HIV-1 broadly neutralizing antibodies (BnAbs) is an attractive strategy. In this study, a recombinant adeno-associated virus 8 (rAAV8) vector was used to encode full-length antibodies against HIV-1 in 293T cells and Balb/c mice after gene transfer. The 10E8 or NIH45-46 BnAb was expressed from a single open reading frame by linking the heavy and light chains with a furin cleavage and a 2A self-processing peptide (F2A)...
November 8, 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27820604/influenza-immunization-elicits-antibodies-specific-for-an-egg-adapted-vaccine-strain
#15
Donald D Raymond, Shaun M Stewart, Jiwon Lee, Jack Ferdman, Goran Bajic, Khoi T Do, Michael J Ernandes, Pirada Suphaphiphat, Ethan C Settembre, Philip R Dormitzer, Giuseppe Del Giudice, Oretta Finco, Tae Hyun Kang, Gregory C Ippolito, George Georgiou, Thomas B Kepler, Barton F Haynes, M Anthony Moody, Hua-Xin Liao, Aaron G Schmidt, Stephen C Harrison
For broad protection against infection by viruses such as influenza or HIV, vaccines should elicit antibodies that bind conserved viral epitopes, such as the receptor-binding site (RBS). RBS-directed antibodies have been described for both HIV and influenza virus, and the design of immunogens to elicit them is a goal of vaccine research in both fields. Residues in the RBS of influenza virus hemagglutinin (HA) determine a preference for the avian or human receptor, α-2,3-linked sialic acid and α-2,6-linked sialic acid, respectively...
November 7, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27815444/an-hiv-1-env-antibody-complex-focuses-antibody-responses-to-conserved-neutralizing-epitopes
#16
Yajing Chen, Richard Wilson, Sijy O'Dell, Javier Guenaga, Yu Feng, Karen Tran, Chi-I Chiang, Heather E Arendt, Joanne DeStefano, John R Mascola, Richard T Wyatt, Yuxing Li
Elicitation of broadly neutralizing Ab (bNAb) responses to the conserved elements of the HIV-1 envelope glycoproteins (Env), including the primary receptor CD4 binding site (CD4bs), is a major focus of vaccine development yet to be accomplished. However, a large number of CD4bs-directed bNAbs have been isolated from HIV-1-infected individuals. Comparison of the routes of binding used by the CD4bs-directed bNAbs from patients and the vaccine-elicited CD4bs-directed mAbs indicates that the latter fail to neutralize primary virus isolates because they approach the Env spike with a vertical angle and contact the specific surface residues occluded in the native spike, including the bridging sheet on gp120...
November 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27807354/hiv-sequential-vaccine-elicits-broadly-neutralizing-antibodies
#17
Alexandra Flemming
No abstract text is available yet for this article.
November 3, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/27807235/molecular-architecture-of-the-cleavage-dependent-mannose-patch-on-a-soluble-hiv-1-envelope-glycoprotein-trimer
#18
Anna-Janina Behrens, David J Harvey, Emilia Milne, Albert Cupo, Abhinav Kumar, Nicole Zitzmann, Weston B Struwe, John P Moore, Max Crispin
: The formation of a correctly folded and natively glycosylated HIV-1 viral spike is dependent on protease cleavage of the gp160 precursor protein in the Golgi apparatus. Cleavage induces a compact structure, which not only renders the spike capable of fusion but also limits further maturation of its extensive glycosylation. The redirection of the glycosylation pathway to preserve underprocessed oligomannose-type glycans is an important feature in immunogen design as glycans contribute to or influence the epitopes of numerous broadly neutralizing antibodies...
November 2, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27806295/differences-in-allelic-frequency-and-cdrh3-region-limit-the-engagement-of-hiv-env-immunogens-by-putative-vrc01-neutralizing-antibody-precursors
#19
Christina Yacoob, Marie Pancera, Vladimir Vigdorovich, Brian G Oliver, Jolene A Glenn, Junli Feng, D Noah Sather, Andrew T McGuire, Leonidas Stamatatos
Elicitation of broadly neutralizing antibodies remains a long-standing goal of HIV vaccine research. Although such antibodies can arise during HIV-1 infection, gaps in our knowledge of their germline, pre-immune precursor forms, as well as on their interaction with viral Env, limit our ability to elicit them through vaccination. Studies of broadly neutralizing antibodies from the VRC01-class provide insight into progenitor B cell receptors (BCRs) that could develop into this class of antibodies. Here, we employed high-throughput heavy chain variable region (VH)/light chain variable region (VL) deep sequencing, combined with biophysical, structural, and modeling antibody analyses, to interrogate circulating potential VRC01-progenitor BCRs in healthy individuals...
November 1, 2016: Cell Reports
https://www.readbyqxmd.com/read/27798403/a-relaxed-directional-random-walk-model-for-phylogenetic-trait-evolution
#20
Mandev S Gill, Lam Si Tung Ho, Guy Baele, Philippe Lemey, Marc A Suchard
Understanding the processes that give rise to quantitative measurements associated with molecular sequence data remains an important issue in statistical phylogenetics. Examples of such measurements include geographic coordinates in the context of phylogeography and phenotypic traits in the context of comparative studies. A popular approach is to model the evolution of continuously varying traits as a Brownian diffusion process acting on a phylogenetic tree. However, standard Brownian diffusion is quite restrictive and may not accurately characterize certain trait evolutionary processes...
October 18, 2016: Systematic Biology
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