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Broadly neutralizing antibodies

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https://www.readbyqxmd.com/read/28088123/antibody-dependent-cellular-cytotoxicity-and-influenza-virus
#1
REVIEW
Hillary A Vanderven, Sinthujan Jegaskanda, Adam K Wheatley, Stephen J Kent
Antibodies are a key defence against influenza infection and disease, but neutralizing antibodies are often strain-specific and of limited utility against divergent or pandemic viruses. There is now considerable evidence that influenza-specific antibodies with Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can assist in the clearance of influenza infection in vitro and in animal models. Further, ADCC-mediating antibodies that recognize a broad array of influenza strains are common in humans, likely as a result of being regularly exposed to influenza infections...
January 11, 2017: Current Opinion in Virology
https://www.readbyqxmd.com/read/28077656/hierarchical-and-redundant-roles-of-activating-fc%C3%AE-rs-in-protection-against-influenza-disease-by-m2e-specific-igg1-and-igg2a-antibodies
#2
Silvie Van den Hoecke, Katrin Ehrhardt, Annasaheb Kolpe, Karim El Bakkouri, Lei Deng, Hendrik Grootaert, Steve Schoonooghe, Anouk Smet, Mostafa Bentahir, Kenny Roose, Michael Schotsaert, Bert Schepens, Nico Callewaert, Falk Nimmerjahn, Peter Staeheli, Hartmut Hengel, Xavier Saelens
: The ectodomain of matrix protein 2 is a universal influenza A vaccine candidate that provides protection through antibody-dependent effector mechanisms. Here we compared the functional engagement of Fcγ Receptor family members by two M2e-specific monoclonal antibodies: mAb 37 (IgG1) and mAb 65 (IgG2a), which recognize a similar epitope in M2e with similar affinity. Binding of mAb 65 to influenza A virus-infected cells triggered all three activating mouse Fcγ receptors in vitro, whereas mAb 37 only activated FcγRIII...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28077654/neutralization-of-diverse-human-cytomegalovirus-strains-conferred-by-antibodies-targets-viral-gh-gl-pul128-131-pentameric-complex
#3
Sha Ha, Fengsheng Li, Matthew C Troutman, Daniel C Freed, Aimin Tang, John W Loughney, Dai Wang, I-Ming Wang, Josef Vlasak, David C Nickle, Richard R Rustandi, Melissa Hamm, Pete A DePhillips, Ningyan Zhang, Jason S McLellan, Hua Zhu, Stuart P Adler, Michael A McVoy, Zhiqiang An, Tong-Ming Fu
: Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection and developing a prophylactic vaccine is of high priority to public health. We recently reported a replication-defective human cytomegalovirus with restored pentameric complex gH/gL/pUL128-131 for prevention of congenital HCMV infection. While the quantity of vaccine-induced antibody responses can be measured in a viral neutralization assay, assessing the quality of such responses, including the ability of vaccine-induced antibodies to cross neutralize the field strains of HCMV, remains a challenge...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28077631/vaccine-efficacy-of-an-inactivated-chimeric-ha-h9-h5n2-avian-influenza-virus-and-its-suitability-for-the-marker-vaccine-strategy
#4
Se Mi Kim, Young-Il Kim, Su-Jin Park, Eun-Ha Kim, Hyeok-Il Kwon, Young-Jae Si, In-Won Lee, Min-Suk Song, Young Ki Choi
: In order to produce a dual effective vaccine against H9 and H5 avian influenza viruses that aligns with the DIVA (differentiating infected from vaccinated animals) strategy, we generated a chimeric H9/H5N2 recombinant vaccine which expressed the whole HA1 region of A/CK/Korea/04163/04 H9N2 and HA2 region of recent HPAI A/MD/Korea/W452/14 H5N8 viruses. The Chimeric H9/H5N2 virus showed similar in vitro and in vivo growth properties and virulence to the LPAI H9 influenza virus. An inactivated vaccine based on this chimeric virus induced serum neutralizing (SN) antibodies against both H9 and H5 viruses, but only induced cross-reactive hemmaglutination inhibition (HI) antibody against H9 viruses...
January 11, 2017: Journal of Virology
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
#5
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
#6
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/28065804/limited-naturally-occurring-escape-in-broadly-neutralizing-antibody-epitopes-in-hepatitis-c-glycoprotein-e2-and-constrained-sequence-usage-in-acute-infection
#7
Chaturaka Rodrigo, Melanie R Walker, Preston Leung, Auda A Eltahla, Jason Grebely, Gregory J Dore, Tanya Applegate, Kimberly Page, Sunita Dwivedi, Julie Bruneau, Meghan D Morris, Andrea L Cox, William Osburn, Arthur Y Kim, Janke Schinkel, Naglaa H Shoukry, Georg M Lauer, Lisa Maher, Margaret Hellard, Maria Prins, Fabio Luciani, Andrew R Lloyd, Rowena A Bull
Broadly neutralizing antibodies have been associated with spontaneous clearance of the hepatitis C infection as well as viral persistence by immune escape. Further study of neutralizing antibody epitopes is needed to unravel pathways of resistance to virus neutralization, and to identify conserved regions for vaccine design. All reported broadly neutralizing antibody (BNAb) epitopes in the HCV Envelope (E2) glycoprotein were identified. The critical contact residues of these epitopes were mapped onto the linear E2 sequence...
January 5, 2017: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/28062126/cross-reactivity-of-immune-responses-to-porcine-reproductive-and-respiratory-syndrome-virus-infection
#8
Ignacio Correas, Fernando A Osorio, David Steffen, Asit K Pattnaik, Hiep L X Vu
Because porcine reproductive and respiratory syndrome virus (PRRSV) exhibits extensive genetic variation among field isolates, characterizing the extent of cross reactivity of immune responses, and most importantly cell-mediated immunity (CMI), could help in the development of broadly cross-protective vaccines. We infected 12 PRRSV-naïve pigs with PRRSV strain FL12 and determined the number of interferon (IFN)-γ secreting cells (SC) by ELISpot assay using ten type 2 and one type 1 PRRSV isolates as recall antigens...
January 3, 2017: Vaccine
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
#9
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
#10
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 4, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28031364/an-optimized-hepatitis-c-virus-e2-glycoprotein-core-adopts-a-functional-homodimer-that-efficiently-blocks-virus-entry
#11
Kathleen McCaffrey, Irene Boo, Catherine M Owczarek, Matthew P Hardy, Matthew A Perugini, Louis Fabri, Pierre Scotney, Pantelis Poumbourios, Heidi E Drummer
: The hepatitis C virus (HCV) envelope glycoprotein E2 is the major target of broadly neutralizing antibodies in vivo and is the focus of efforts in the rational design of a universal B cell vaccine against HCV. The E2 glycoprotein exhibits a high degree of amino-acid variability which localizes to three discrete regions: hypervariable region 1 (HVR1), hypervariable region 2 (HVR2) and the intergenotypic variable region (igVR). All three variable regions contribute to immune evasion and/or isolate-specific structural variations, both important considerations for vaccine design...
December 28, 2016: Journal of Virology
https://www.readbyqxmd.com/read/28011932/immunodominance-of-antibody-recognition-of-the-hiv-envelope-v2-region-in-ig-humanized-mice
#12
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/28003465/structural-basis-of-influenza-virus-fusion-inhibition-by-the-antiviral-drug-arbidol
#13
Rameshwar U Kadam, Ian A Wilson
The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers...
December 21, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28003309/progress-toward-active-or-passive-hiv-1-vaccination
#14
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/28000522/targeting-the-interferon-pathway-with-sifalimumab-for-the-treatment-of-systemic-lupus-erythematosus
#15
Warren Greth, Gabriel J Robbie, Philip Brohawn, Micki Hultquist, Bing Yao
Dysregulation of the type I interferon (IFN) system is associated with various immunologic diseases, such as systemic lupus erythematosus (SLE). Targeting this dysregulation presents an attractive approach for SLE therapy. Sifalimumab, a fully human immunoglobulin G1 κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes, has been recently evaluated in a Phase IIb study in patients with moderate to severe SLE. Insights gained from earlier studies were used to inform design of the Phase IIb study, to provide a more comprehensive evaluation of sifalimumab...
January 2017: Immunotherapy
https://www.readbyqxmd.com/read/27997681/the-core-domain-of-hepatitis-c-virus-glycoprotein-e2-generates-potent-cross-neutralizing-antibodies
#16
Patricia Vietheer, Irene Boo, Jun Gu, Kathleen McCaffrey, Stirling Edwards, Catherine Owczarek, Matthew P Hardy, Louis Fabri, Rob J Center, Pantelis Poumbourios, Heidi E Drummer
: A vaccine that prevents hepatitis C virus (HCV) infection is urgently needed to support an emerging global elimination program. However, vaccine development has been confounded because of HCV's high degree of antigenic variability and the preferential induction of type-specific immune responses with limited potency against heterologous viral strains and genotypes. We showed previously that deletion of the three variable regions from the E2 receptor-binding domain (Δ123) increases the ability of human broadly neutralizing antibodies (bNAbs) to inhibit E2-CD81 receptor interactions, suggesting improved bNAb epitope exposure...
December 20, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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
#17
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
#18
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
#19
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/27966523/functional-screening-for-anti-cmv-biologics-identifies-a-broadly-neutralizing-epitope-of-an-essential-envelope-protein
#20
Thomas J Gardner, Kathryn R Stein, J Andrew Duty, Toni M Schwarz, Vanessa M Noriega, Thomas Kraus, Thomas M Moran, Domenico Tortorella
The prototypic β-herpesvirus human cytomegalovirus (CMV) establishes life-long persistence within its human host. The CMV envelope consists of various protein complexes that enable wide viral tropism. More specifically, the glycoprotein complex gH/gL/gO (gH-trimer) is required for infection of all cell types, while the gH/gL/UL128/130/131a (gH-pentamer) complex imparts specificity in infecting epithelial, endothelial and myeloid cells. Here we utilize state-of-the-art robotics and a high-throughput neutralization assay to screen and identify monoclonal antibodies (mAbs) targeting the gH glycoproteins that display broad-spectrum properties to inhibit virus infection and dissemination...
December 14, 2016: Nature Communications
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