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Hiv and broadly neutralizing antibody

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https://www.readbyqxmd.com/read/28095712/current-views-on-the-potential-for-development-of-a-hiv-vaccine
#1
Kristen W Cohen, Nicole Frahm
Despite many recent advances in the HIV prevention landscape, an effective vaccine remains the most promising tool to end the HIV-1 pandemic. Areas covered: This review summarizes past HIV vaccine efficacy trials and current vaccine strategies as well as new approaches about to move into first-in-human trials. Expert opinion: Despite many setbacks in early HIV vaccine efficacy trials, the success of RV144 has provided the glimmer of hope necessary to invigorate the vaccine field, and has led to the development of a large number of vaccine strategies aiming at inducing an array of different immune responses...
January 18, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28076415/structure-and-recognition-of-a-novel-hiv-1-gp120-gp41-interface-antibody-that-caused-mper-exposure-through-viral-escape
#2
Constantinos Kurt Wibmer, Jason Gorman, Gabriel Ozorowski, Jinal N Bhiman, Daniel J Sheward, Debra H Elliott, Julie Rouelle, Ashley Smira, M Gordon Joyce, Nonkululeko Ndabambi, Aliaksandr Druz, Mangai Asokan, Dennis R Burton, Mark Connors, Salim S Abdool Karim, John R Mascola, James E Robinson, Andrew B Ward, Carolyn Williamson, Peter D Kwong, Lynn Morris, Penny L Moore
A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28073404/isolation-and-characterization-of-hiv-1-envelope-glycoprotein-specific-b-cell-from-immortalized-human-na%C3%A3-ve-b-cell-library
#3
Zehua Sun, Shiqiang Lu, Zheng Yang, Jingjing Li, Meiyun Zhang
With the recent development of single B cell cloning techniques, an increasing number of HIV-1-specific broadly neutralizing antibodies (bNAbs) have been isolated since 2009. However, knowledge regarding HIV-1-specific B cells in vivo is limited. In this study, an HIV-1-specific B cell line has been established using healthy PBMC donors by the highly efficient EBV transformation method to generate immortalized human naïve B cell libraries. The enrichment of HIV-1 envelope-specific B cells was observed after four rounds of cell panning with the HIV-1 envelope glycoprotein...
January 10, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28060015/ifn-%C3%AE-augments-nk-mediated-antibody-dependent-cellular-cytotoxicity-adcc-of-hiv-1-infected-autologous-cd4-t-cells-regardless-of-mhc-i-downregulation
#4
Costin Tomescu, Pablo Tebas, Luis J Montaner
DESIGN: We have previously shown that IFN-α stimulation augments direct NK cell lysis of autologous CD4 primary T cells infected with certain HIV-1 isolates based upon MHC-I downregulation capacity. Here, we investigated if Antibody Dependent Cellular Cytotoxicity (ADCC) could trigger lysis of HIV-1 isolates that were resistant to direct NK lysis and if IFN-α pre-stimulation of NK cells could further enhance ADCC. METHODS: Using broadly neutralizing monoclonal antibodies against gp120 (VRC01 or PGV04) or plasma from HIV-1 infected subjects (ART-suppressed or Elite Controller) to trigger ADCC, we measured NK cell chromium release cytotoxicity against HIV-1 infected autologous CD4 primary T cells and NK cell CD107a degranulation against gp120-coated CD4 T cells...
January 4, 2017: AIDS
https://www.readbyqxmd.com/read/28052137/mapping-polyclonal-hiv-1-antibody-responses-via-next-generation-neutralization-fingerprinting
#5
Nicole A Doria-Rose, Han R Altae-Tran, Ryan S Roark, Stephen D Schmidt, Matthew S Sutton, Mark K Louder, Gwo-Yu Chuang, Robert T Bailer, Valerie Cortez, Rui Kong, Krisha McKee, Sijy O'Dell, Felicia Wang, Salim S Abdool Karim, James M Binley, Mark Connors, Barton F Haynes, Malcolm A Martin, David C Montefiori, Lynn Morris, Julie Overbaugh, Peter D Kwong, John R Mascola, Ivelin S Georgiev
Computational neutralization fingerprinting, NFP, is an efficient and accurate method for predicting the epitope specificities of polyclonal antibody responses to HIV-1 infection. Here, we present next-generation NFP algorithms that substantially improve prediction accuracy for individual donors and enable serologic analysis for entire cohorts. Specifically, we developed algorithms for: (a) selection of optimized virus neutralization panels for NFP analysis, (b) estimation of NFP prediction confidence for each serum sample, and (c) identification of sera with potentially novel epitope specificities...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28011932/immunodominance-of-antibody-recognition-of-the-hiv-envelope-v2-region-in-ig-humanized-mice
#6
Kevin Wiehe, Nathan I Nicely, Bradley Lockwood, Masayuki Kuraoka, Kara Anasti, Sabrina Arora, Cindy M Bowman, Christina Stolarchuk, Robert Parks, Krissey E Lloyd, Shi-Mao Xia, Ryan Duffy, Xiaoying Shen, Christos A Kyratsous, Lynn E Macdonald, Andrew J Murphy, Richard M Scearce, M Anthony Moody, S Munir Alam, Laurent Verkoczy, Georgia D Tomaras, Garnett Kelsoe, Barton F Haynes
In the RV144 gp120 HIV vaccine trial, decreased transmission risk was correlated with Abs that reacted with a linear epitope at a lysine residue at position 169 (K169) in the HIV-1 envelope (Env) V2 region. The K169 V2 response was restricted to Abs bearing Vλ rearrangements that expressed aspartic acid/glutamic acid in CDR L2. The AE.A244 gp120 in AIDSVAX B/E also bound to the unmutated ancestor of a V2-glycan broadly neutralizing Ab, but this Ab type was not induced in the RV144 trial. In this study, we sought to determine whether immunodominance of the V2 linear epitope could be overcome in the absence of human Vλ rearrangements...
December 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28003309/progress-toward-active-or-passive-hiv-1-vaccination
#7
REVIEW
Amelia Escolano, Pia Dosenovic, Michel C Nussenzweig
AIDS is a preventable disease. Nevertheless, according to UNAIDS, 2.1 million individuals were infected with HIV-1 in 2015 worldwide. An effective vaccine is highly desirable. Most vaccines in clinical use today prevent infection because they elicit antibodies that block pathogen entry. Consistent with this general rule, studies in experimental animals have shown that broadly neutralizing antibodies to HIV-1 can prevent infection, suggesting that a vaccine that elicits such antibodies would be protective. However, despite significant efforts over the last 30 years, attempts to elicit broadly HIV-1 neutralizing antibodies by vaccination failed until recent experiments in genetically engineered mice were finally successful...
January 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27996375/trimeric-gp120-specific-bovine-monoclonal-antibodies-require-cysteine-and-aromatic-residues-in-cdrh3-for-high-affinity-binding-to-hiv-env
#8
Behnaz Heydarchi, Rob J Center, Jonathan Bebbington, Jack Cuthbertson, Christopher Gonelli, Georges Khoury, Charlene Mackenzie, Marit Lichtfuss, Grant Rawlin, Brian Muller, Damian Purcell
We isolated HIV-1 Envelope (Env)-specific memory B cells from a cow that had developed high titre polyclonal immunoglobulin G (IgG) with broad neutralizing activity after a long duration vaccination with HIV-1AD8 Env gp140 trimers. We cloned the bovine IgG matched heavy (H) and light (L) chain variable (V) genes from these memory B cells and constructed IgG monoclonal antibodies (mAbs) with either a human constant (C)-region/bovine V-region chimeric or fully bovine C and V regions. Among 42 selected Ig+ memory B cells, two mAbs (6A and 8C) showed high affinity binding to gp140 Env...
December 20, 2016: MAbs
https://www.readbyqxmd.com/read/27984693/global-n-glycan-site-occupancy-of-hiv-1-gp120-by-metabolic-engineering-and-high-resolution-intact-mass-spectrometry
#9
Weston B Struwe, Alexandra Stuckmann, Anna-Janina Behrens, Kevin Pagel, Max Crispin
A vital step in HIV vaccine development strategies has been the observation that some infected individuals generate broadly neutralizing antibodies that target the glycans on the surface of HIV-1 gp120. These antibodies target glycan epitopes on viral envelope spikes, and yet the positions and degree of occupancy of glycosylation sites is diverse. Therefore, there is a need to understand glycosylation occupancy on recombinant immunogens. The sheer number of potential glycosylation sites and degree of chemical heterogeneity impedes assessing the global sequon occupancy of gp120 glycoforms...
January 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/27966557/broadly-neutralizing-antibodies-suppress-post-transcytosis-hiv-1-infectivity
#10
V Lorin, M Malbec, C Eden, T Bruel, F Porrot, M S Seaman, O Schwartz, H Mouquet
Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection in humans. Immunoprophylaxis with potent bNAbs efficiently protects non-human primates from mucosal transmission even after repeated challenges. However, the precise mechanisms of bNAb-mediated viral inhibition in mucosal tissues are currently unknown. Here, we show that immunoglobulin (Ig)G and IgA bNAbs do not interfere with the endocytic transport of HIV-1 across epithelial cells, a process referred to as transcytosis...
December 14, 2016: Mucosal Immunology
https://www.readbyqxmd.com/read/27959955/experimental-estimation-of-the-effects-of-all-amino-acid-mutations-to-hiv-s-envelope-protein-on-viral-replication-in-cell-culture
#11
Hugh K Haddox, Adam S Dingens, Jesse D Bloom
HIV is notorious for its capacity to evade immunity and anti-viral drugs through rapid sequence evolution. Knowledge of the functional effects of mutations to HIV is critical for understanding this evolution. HIV's most rapidly evolving protein is its envelope (Env). Here we use deep mutational scanning to experimentally estimate the effects of all amino-acid mutations to Env on viral replication in cell culture. Most mutations are under purifying selection in our experiments, although a few sites experience strong selection for mutations that enhance HIV's replication in cell culture...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27959740/broadly-neutralizing-antibodies-for-hiv-1-prevention-or-immunotherapy
#12
Marina Caskey, Florian Klein, Michel C Nussenzweig
No abstract text is available yet for this article.
November 24, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27959728/effect-of-hiv-antibody-vrc01-on-viral-rebound-after-treatment-interruption
#13
MULTICENTER STUDY
Katharine J Bar, Michael C Sneller, Linda J Harrison, J Shawn Justement, Edgar T Overton, Mary E Petrone, D Brenda Salantes, Catherine A Seamon, Benjamin Scheinfeld, Richard W Kwan, Gerald H Learn, Michael A Proschan, Edward F Kreider, Jana Blazkova, Mark Bardsley, Eric W Refsland, Michael Messer, Katherine E Clarridge, Nancy B Tustin, Patrick J Madden, KaSaundra Oden, Sijy J O'Dell, Bernadette Jarocki, Andrea R Shiakolas, Randall L Tressler, Nicole A Doria-Rose, Robert T Bailer, Julie E Ledgerwood, Edmund V Capparelli, Rebecca M Lynch, Barney S Graham, Susan Moir, Richard A Koup, John R Mascola, James A Hoxie, Anthony S Fauci, Pablo Tebas, Tae-Wook Chun
Background The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). Methods We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART...
November 24, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27943074/eliciting-10e8-like-antibodies-by-the-membrane-proximal-external-region-peptide-of-hiv-1-in-guinea-pigs
#14
Yongjiao Yu, Lu Fu, Xin Gong, Shanshan Guan, Xiaoqiu He, He Yin, Ziyu Kuai, Wei Kong, Yuhua Shi, Yaming Shan
OBJECTIVE: To develop an immunotherapy for HIV that can elicit 10E8-like broadly-neutralizing antibodies in guinea pigs, using a multiple antigen peptide (MAP) system as the platform and 10E8 peptide as the epitope. RESULTS: The immunogen, 10E8-MAP4, was synthetized using the MAP system. The synthetic 10E8-MAP4 was stable, and the epitopes could be exposed for recognition. In addition, the 10E8 epitope was present in an α-helical structure, which was hypothesized to aid in the generation of neutralizing antibodies...
December 10, 2016: Biotechnology Letters
https://www.readbyqxmd.com/read/27939012/immunofocusing-using-conformationally-constrained-v3-peptide-immunogens-improves-hiv-1-neutralization
#15
Adi Moseri, Eshu Sinha, Henni Zommer, Boris Arshava, Fred Naider, Jacob Anglister
V3-directed antibodies are present in practically all HIV-1 infected patients and in individuals vaccinated with gp120. The levels of maternal V3-directed antibodies were recently shown to correlate with reduced mother to child transmission, and V3 IgGs were found to be a negative correlate of risk in the RV-144 human trial. mAb directed to the tip of the V3 are capable of broad neutralization of Tier-1 and some Tier-2 viruses. Here we report an immunofocusing approach using conformationally constrained V3 peptides of different lengths...
January 5, 2017: Vaccine
https://www.readbyqxmd.com/read/27938646/increased-frequencies-of-cd8-cd57-t-cells-are-associated-with-antibody-neutralization-breadth-against-hiv-in-viraemic-controllers
#16
Christine D Palmer, Marisol Romero-Tejeda, Eileen P Scully, Ainsley Lockhart, Michael S Seaman, Ariel Goldenthal, Alicja Piechocka-Trocha, Bruce D Walker, Lori B Chibnik, Stephanie Jost, Filippos Porichis
INTRODUCTION: An effective prophylactic vaccine against HIV will need to elicit antibody responses capable of recognizing and neutralizing rapidly evolving antigenic regions. The immunologic milieu associated with development of neutralizing antibody breadth remains to be fully defined. In this study, we sought to identify immunological signatures associated with neutralization breadth in HIV controllers. We applied an immune monitoring approach to analyze markers of T cell and myeloid cell activation by flow cytometry, comparing broad neutralizers with low- and non-neutralizers using multivariate and univariate analyses...
2016: Journal of the International AIDS Society
https://www.readbyqxmd.com/read/27928004/the-effect-of-hiv-1-env-on-serinc5-antagonism
#17
Saina Beitari, Shilei Ding, Qinghua Pan, Andrés Finzi, Chen Liang
: SERINC5 is able to restrict HIV-1 infection by drastically impairing the infectivity of viral particles. Current studies have shown that HIV-1 Nef protein counters SERINC5 through down regulating SERINC5 from the cell surface and preventing virion incorporation of SERINC5. In addition, the Env proteins of some HIV-1 strains can also overcome SERINC5 inhibition. However, it is unclear how HIV-1 Env does so and why HIV-1 has two mechanisms to resist SERINC5 inhibition. Results of this study show that neither Env nor Nef prevents high-level ectopic SERINC5 from incorporation into HIV-1 particles, except that Env, but not Nef, is able to resist the inhibition of virion-associated SERINC5...
December 7, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27919754/neutralization-takes-precedence-over-igg-or-iga-isotype-related-functions-in-mucosal-hiv-1-antibody-mediated-protection
#18
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...
December 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
#19
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
#20
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
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