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Broad neutralizing antibody

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https://www.readbyqxmd.com/read/28943879/plasma-cxcl13-but-not-b-cell-frequencies-in-acute-hiv-infection-predicts-emergence-of-cross-neutralizing-antibodies
#1
Jenniffer M Mabuka, Anne-Sophie Dugast, Daniel M Muema, Tarylee Reddy, Yathisha Ramlakhan, Zelda Euler, Nasreen Ismail, Amber Moodley, Krista L Dong, Lynn Morris, Bruce D Walker, Galit Alter, Thumbi Ndung'u
Immunological events in acute HIV-1 infection before peak viremia (hyperacute phase) may contribute to the development of broadly cross-neutralizing antibodies. Here, we used pre-infection and acute-infection peripheral blood mononuclear cells and plasma samples from 22 women, including 10 who initiated antiretroviral treatment in Fiebig stages I-V of acute infection to study B cell subsets and B-cell associated cytokines (BAFF and CXCL13) kinetics for up to ~90 days post detection of plasma viremia. Frequencies of B cell subsets were defined by flow cytometry while plasma cytokine levels were measured by ELISA...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28941873/extracorporeal-life-support-and-digoxin-specific-fab-fragments-for-successful-management-of-taxus-baccata-intoxication-with-low-output-and-ventricular-arrhythmia
#2
Mina Farag, Dominika Badowski, Ronald Koschny, Gisela Skopp, Andreas Brcic, Gabor B Szabo
INTRODUCTION: Yew plants are evergreen shrubs which are widely spread throughout the northern hemisphere. Taxane alkaloid derivatives, mainly taxine B, represent the main toxins of Taxus baccata and are highly cardiotoxic. Due to the lack of randomized clinical trials, case reports on accidental or suicidal yew intoxications build the only source of knowledge of clinical treatment options. CASE REPORT: We report the case of a suicidal yew ingestion admitted to our hospital under prolonged cardiopulmonary resuscitation due to pulseless electrical activity...
September 18, 2017: American Journal of Emergency Medicine
https://www.readbyqxmd.com/read/28938888/unique-binding-modes-for-the-broad-neutralizing-activity-of-single-chain-variable-fragments-scfv-targeting-cd4-induced-epitopes
#3
Kazuki Tanaka, Takeo Kuwata, Muntasir Alam, Gilad Kaplan, Shokichi Takahama, Kristel Paola Ramirez Valdez, Anna Roitburd-Berman, Jonathan M Gershoni, Shuzo Matsushita
BACKGROUND: The CD4-induced (CD4i) epitopes in gp120 includes the co-receptor binding site, which are formed and exposed after interaction with CD4. Monoclonal antibodies (mAbs) to the CD4i epitopes exhibit limited neutralizing activity because of restricted access to their epitopes. However, small fragment counterparts such as single-chain variable fragments (scFvs) have been reported to neutralize a broad range of viruses compared with the full-size IgG molecule. To identify the CD4i epitope site responsible for this broad neutralization we constructed three scFvs of anti-CD4i mAbs from a human immunodeficiency virus type 1 (HIV-1)-infected elite controller, and investigated the neutralization coverage and precise binding site in the CD4i epitopes...
September 22, 2017: Retrovirology
https://www.readbyqxmd.com/read/28935113/directed-evolution-of-glycopeptides-using-mrna-display
#4
Satoru Horiya, Jennifer K Bailey, Isaac J Krauss
Directed evolution is a useful method for the discovery of nucleic acids, peptides, or proteins that have desired binding abilities or functions. Because of the abundance and importance of glycosylation in nature, directed evolution of glycopeptides and glycoproteins is also highly desirable. However, common directed evolution platforms such as phage-, yeast-, or mammalian-cell display are limited for these applications by several factors. Glycan structure at each glycosylation site is not genetically encoded, and yeast and mammalian cells produce a heterogeneous mixture of glycoforms at each site on the protein...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28933684/screening-of-primary-gp120-immunogens-to-formulate-the-next-generation-polyvalent-dna-prime-protein-boost-hiv-1-vaccines
#5
Shixia Wang, Te-Hui Wu, Anthony Hackett, Veronica Efros, Yan Wang, Dong Han, Aaron Wallace, Yuxin Chen, Guangnan Hu, Shuying Liu, Paul Clapham, James Arthos, David Montefiori, Shan Lu
Our previous preclinical studies and a Phase I clinical trial DP6-001 have indicated that a polyvalent Env formulation was able to elicit broadly reactive antibody responses including low titer neutralizing antibody responses against viral isolates of subtypes A, B, C and AE. In the current report, a panel of 62 gp120 immunogens were screened in a rabbit model to identify gp120 immunogens that can elicit improved binding and neutralizing antibody responses and some of them can be included in the next polyvalent formulation...
September 21, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28931763/reversible-retinal-vessel-closure-from-vegf-induced-leukocyte-plugging
#6
Yuanyuan Liu, Jikui Shen, Seth D Fortmann, Jiangxia Wang, Dietmar Vestweber, Peter A Campochiaro
Clinical trials in patients with macular edema due to diabetic retinopathy or retinal vein occlusion (RVO) have shown that suppression of VEGF not only improves macular edema, but also reopens closed retinal vessels, prevents progression of vessel closure, and improves retinopathy. In this study, we show the molecular basis for those clinical observations. Increased retinal levels of VEGF in mice cause plugging of retinal vessels with leukocytes, vessel closure, and hypoxia. Suppression of VEGF reduces leukocyte plugging, causing reperfusion of closed vessels...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931655/protection-against-a-mixed-shiv-challenge-by-a-broadly-neutralizing-antibody-cocktail
#7
Boris Julg, Po-Ting Liu, Kshitij Wagh, William M Fischer, Peter Abbink, Noe B Mercado, James B Whitney, Joseph P Nkolola, Katherine McMahan, Lawrence J Tartaglia, Erica N Borducchi, Shreeya Khatiwada, Megha Kamath, Jake A LeSuer, Michael S Seaman, Stephen D Schmidt, John R Mascola, Dennis R Burton, Bette T Korber, Dan H Barouch
HIV-1 sequence diversity presents a major challenge for the clinical development of broadly neutralizing antibodies (bNAbs) for both therapy and prevention. Sequence variation in critical bNAb epitopes has been observed in most HIV-1-infected individuals and can lead to viral escape after bNAb monotherapy in humans. We show that viral sequence diversity can limit both the therapeutic and prophylactic efficacy of bNAbs in rhesus monkeys. We first demonstrate that monotherapy with the V3 glycan-dependent antibody 10-1074, but not PGT121, results in rapid selection of preexisting viral variants containing N332/S334 escape mutations and loss of therapeutic efficacy in simian-HIV (SHIV)-SF162P3-infected rhesus monkeys...
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28931639/trispecific-broadly-neutralizing-hiv-antibodies-mediate-potent-shiv-protection-in-macaques
#8
Ling Xu, Amarendra Pegu, Ercole Rao, Nicole Doria-Rose, Jochen Beninga, Krisha McKee, Dana M Lord, Ronnie R Wei, Gejing Deng, Mark Louder, Stephen D Schmidt, Zachary Mankoff, Lan Wu, Mangaiarkarasi Asokan, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Jochen Kruip, Rebecca Sendak, Young Do Kwon, Tongqing Zhou, Xuejun Chen, Robert T Bailer, Keyun Wang, Misook Choe, Lawrence J Tartaglia, Dan H Barouch, Sijy O'Dell, John-Paul Todd, Dennis R Burton, Mario Roederer, Mark Connors, Richard A Koup, Peter D Kwong, Zhi-Yong Yang, John R Mascola, Gary J Nabel
The development of an effective AIDS vaccine has been challenging due to viral genetic diversity and the difficulty in generating broadly neutralizing antibodies (bnAbs). Here, we engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: 1) the CD4 binding site, 2) the membrane proximal external region (MPER) and 3) the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to human bnAbs, and conferred complete immunity against a mixture of SHIVs in non-human primates (NHP) in contrast to single bnAbs...
September 20, 2017: Science
https://www.readbyqxmd.com/read/28930686/antibody-27f3-broadly-targets-influenza-a-group-1-and-2-hemagglutinins-through-a-further-variation-in-vh1-69-antibody-orientation-on-the-ha-stem
#9
Shanshan Lang, Jia Xie, Xueyong Zhu, Nicholas C Wu, Richard A Lerner, Ian A Wilson
Antibodies that target both group 1 and group 2 influenza A viruses are valuable for therapeutic and vaccine development, but only a few have been reported to date. Here, we describe a new VH1-69 antibody 27F3 that broadly recognizes heterosubtypic hemagglutinins (HAs) from both group 1 and group 2 influenza A viruses. Structural characterization of 27F3 Fab with A/California/04/2009 (H1N1) hemagglutinin illustrates that 27F3 shares the key binding features observed in other VH1-69 antibodies to the HA stem...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28929430/new-drugs-in-the-pipeline-for-the-treatment-of-hiv-a-review
#10
REVIEW
Leigh Anne Hylton Gravatt, Crystal R Leibrand, Sulay Patel, MaryPeace McRae
PURPOSE OF REVIEW: The purpose of this paper is to review therapies with new mechanisms of action for the treatment of HIV that are at least in phase 2 clinical trials. RECENT FINDINGS: There are several new mechanisms of action being represented within clinical development, including histone deacetylase (HDAC) inhibitors, gene therapies, broadly neutralizing anti-HIV antibodies, immune modulation, and drugs with new mechanisms to block HIV entry. The new therapies are being developed for both as add-on therapy to existing combination antiretroviral therapy and as agents to be used during treatment interruption...
September 19, 2017: Current Infectious Disease Reports
https://www.readbyqxmd.com/read/28928737/env-specific-antibodies-in-chronic-infection-versus-in-vaccination
#11
REVIEW
Martina Soldemo, Gunilla B Karlsson Hedestam
Antibodies are central in vaccine-mediated protection. For HIV-1, a pathogen that displays extreme antigenic variability, B cell responses against conserved determinants of the envelope glycoproteins (Env) are likely required to achieve broadly protective vaccine-induced responses. To understand antibodies in chronic infection, where broad serum neutralizing activity is observed in a subset of individuals, monoclonal antibodies mediating this activity have been isolated. Studies of their maturation pathways reveal that years of co-evolution between the virus and the adaptive immune response are required for such responses to arise...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28928416/zika-virus-infection-confers-protection-against-west-nile-virus-challenge-in-mice
#12
Ángela Vázquez-Calvo, Ana-Belén Blázquez, Estela Escribano-Romero, Teresa Merino-Ramos, Juan-Carlos Saiz, Miguel A Martín-Acebes, Nereida Jiménez de Oya
Flaviviruses are RNA viruses that constitute a worrisome threat to global human and animal health. Zika virus (ZIKV), which was initially reported to cause a mild disease, recently spread in the Americas, infecting millions of people. During this recent epidemic, ZIKV infection has been linked to serious neurological diseases and birth defects, specifically Guillain-Barrè syndrome (GBS) and microcephaly. Because information about ZIKV immunity remains scarce, we assessed the humoral response of immunocompetent mice to infection with three viral strains of diverse geographical origin (Africa, Asia and America)...
September 20, 2017: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/28926408/serum-glycan-binding-igg-antibodies-in-hiv-1-infection-and-during-the-development-of-broadly-neutralizing-responses
#13
Cathrine Scheepers, Sudipa Chowdhury, W Shea Wright, Christopher T Campbell, Nigel J Garrett, Quarraisha Abdool Karim, Salim S Abdool Karim, Penny L Moore, Jeffrey C Gildersleeve, Lynn Morris
BACKGROUND: The HIV-1 envelope is covered with glycans that provide structural integrity and protect conserved regions from host antibody responses. However, these glycans are often the target of broadly neutralizing antibodies (bNAbs) that emerge in some HIV infected individuals. We aimed to determine whether anti-glycan IgG antibodies are a general response to HIV-1 infection or specific to individuals who develop bNAbs. METHODS: IgG binding to glycans was assessed using arrays that contained 245 unique components including N-linked carbohydrates, glycolipids and Tn-peptides...
September 18, 2017: AIDS
https://www.readbyqxmd.com/read/28926399/natural-killer-cells-in-hiv-1-infection-and-therapy
#14
Joanna Mikulak, Ferdinando Oriolo, Elisa Zaghi, Clara Di Vito, Domenico Mavilio
: Natural killer (NK) cells are important effectors of innate immunity playing a key role in the eradication and clearance of viral infections. Over the recent years, several studies have shown that HIV-1 pathologically changes NK cell homeostasis and hampers their antiviral effector functions. Moreover, high levels of chronic HIV-1 viremia markedly impair those NK cell regulatory features that normally regulate the cross-talks between innate and adaptive immune responses. These pathogenic events take place early in the infection and are associated with a pathologic redistribution of NK cell subsets that includes the expansion of anergic CD56 NK cells with an aberrant repertoire of activating and inhibitory receptors...
September 18, 2017: AIDS
https://www.readbyqxmd.com/read/28925296/vaccine-approaches-conferring-cross-protection-against-influenza-viruses
#15
Sai V Vemula, Ekramy E Sayedahmed, Suryaprakash Sambhara, Suresh K Mittal
Annual vaccination is one of the most efficient and cost-effective strategies to prevent and control influenza epidemics. Most of the currently available influenza vaccines are strong inducers of antibody responses against viral surface proteins, hemagglutinin (HA) and neuraminidase (NA), but are poor inducers of cell-mediated immune responses against conserved internal proteins. Moreover, due to the high variability of viral surface proteins because of antigenic drift or antigenic shift, many of the currently licensed vaccines confer little or no protection against drift or shift variants...
September 19, 2017: Expert Review of Vaccines
https://www.readbyqxmd.com/read/28922082/combinatorial-peptide-based-epitope-mapping-from-ebola-virus-dna-vaccines-and-infections-reveals-residue-level-determinants-of-antibody-binding
#16
Daniel R Ripoll, Daniel A J Mitchell, Lesley C Dupuy, Anders Wallqvist, Connie Schmaljohn, Sidhartha Chaudhury
Ebola virus (EBOV) infection is highly lethal and results in severe febrile bleeding disorders that affect humans and non-human primates. One of the therapeutic approaches for treating EBOV infection focus largely on cocktails of monoclonal antibodies (mAbs) that bind to specific regions of the EBOV glycoprotein (GP) and neutralize the virus. Recent structural studies using cryo-electron microscopy have identified key epitopes for several EBOV mAbs. While such information has yielded deep insights into antibody binding, limitations on resolution of these structures often preclude a residue-level analysis of EBOV epitopes...
September 18, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28918477/in-vitro-inhibition-of-hiv-1-replication-in-autologous-cd4-t-cells-indicates-viral-containment-by-multifactorial-mechanisms
#17
Ting Tu, Jianbo Zhan, Danlei Mou, Wei Li, Bin Su, Tong Zhang, Tao Li, Ning Li, Hao Wu, Cong Jin, Huabiao Chen
HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies (NAbs) are present during chronic infection, but the relative contributions of these effector mechanisms to viral containment remain unclear. Here, using an in vitro model involving autologous CD4(+) T cells, primary HIV-1 isolates, HIV-1-specific CTLs, and neutralizing monoclonal antibodies, we show that b12, a potent and broadly neutralizing monoclonal antibody to HIV-1, was able to block viral infection when preincubated with virus prior to infection, but was much less effective than CTLs at limiting virus replication when added to infected cell cultures...
September 15, 2017: Virologica Sinica
https://www.readbyqxmd.com/read/28916265/glycans-function-as-anchors-for-antibodies-and-help-drive-hiv-broadly-neutralizing-antibody-development
#18
Raiees Andrabi, Ching-Yao Su, Chi-Hui Liang, Sachin S Shivatare, Bryan Briney, James E Voss, Salar Khan Nawazi, Chung-Yi Wu, Chi-Huey Wong, Dennis R Burton
Apex broadly neutralizing HIV antibodies (bnAbs) recognize glycans and protein surface close to the 3-fold axis of the envelope (Env) trimer and are among the most potent and broad Abs described. The evolution of apex bnAbs from one donor (CAP256) has been studied in detail and many Abs at different stages of maturation have been described. Using diverse engineering tools, we investigated the involvement of glycan recognition in the development of the CAP256.VRC26 Ab lineage. We found that sialic acid-bearing glycans were recognized by germline-encoded and somatically mutated residues on the Ab heavy chain...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28910287/generation-of-a-serum-free-cho-dg44-cell-line-stably-producing-a-broadly-protective-anti-influenza-virus-monoclonal-antibody
#19
Veronika Chromikova, Maria A Zaragoza, Florian Krammer
Because of the broad neutralization and in vivo protection across influenza A and influenza B virus strains, monoclonal antibody CR9114 is widely used in influenza virus research as a positive control in many experiments. To produce amounts sufficient for the demand requires regular transient transfections, resulting in varying yield as well as differing batch to batch quality. Here, we report the development of a serum-free CHO DG44 cell line, stably producing a CR9114-like antibody with a potential to become a useful influenza virus research tool...
2017: PloS One
https://www.readbyqxmd.com/read/28903577/a-2-4-amino-acid-deletion-in-the-v5-region-of-hiv-1-env-gp120-confers-viral-resistance-to-the-broadly-neutralizing-human-monoclonal-antibody-vrc01
#20
Shingo Tachibana, Maho Sasaki, Takako Tanaka, Mari Inoue, Youdiil Ophinni, Tomohiro Kotaki, Masanori Kameoka
The envelope glycoprotein (Env) gp120 of human immunodeficiency virus type 1 (HIV-1) plays a critical role in viral entry into host cells. The broadly neutralizing human monoclonal antibody VRC01, which recognizes the CD4 binding site on gp120, neutralizes more than 90% of HIV-1 isolates. However, some of the CRF01_AE viruses prevalent in Southeast Asia are resistant to VRC01-mediated neutralization. We previously reported that 3 amino acid residues at positions 185, 186, and 197 of gp120 played an important role in the VRC01 resistance of CRF01_AE Env (AE-Env) clones isolated from HIV-infected Thai individuals...
September 13, 2017: AIDS Research and Human Retroviruses
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