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Hiv and broadly neutralizing antibody

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https://www.readbyqxmd.com/read/29784645/harnessing-post-translational-modifications-for-next-generation-hiv-immunogens
#1
REVIEW
Joel D Allen, Rogier W Sanders, Katie J Doores, Max Crispin
The extensive post-translational modifications of the envelope spikes of the human immunodeficiency virus (HIV) present considerable challenges and opportunities for HIV vaccine design. These oligomeric glycoproteins typically have over 30 disulfide bonds and around a 100 N-linked glycosylation sites, and are functionally dependent on protease cleavage within the secretory system. The resulting mature structure adopts a compact fold with the vast majority of its surface obscured by a protective shield of glycans which can be targeted by broadly neutralizing antibodies (bnAbs)...
May 21, 2018: Biochemical Society Transactions
https://www.readbyqxmd.com/read/29775847/strategies-for-a-multi-stage-neutralizing-antibody-based-hiv-vaccine
#2
REVIEW
Raiees Andrabi, Jinal N Bhiman, Dennis R Burton
A critical property of a prophylactic HIV vaccine is likely to be its ability to elicit broadly neutralizing antibodies (bnAbs). BnAbs typically have multiple unusual features and are generated in a fraction of HIV-infected individuals through complex pathways. Current vaccine design approaches seek to trigger rare B cell precursors and then steer affinity maturation toward bnAbs in a multi-stage multi-component immunization approach. These vaccine design strategies have been facilitated by molecular descriptions of bnAb interactions with stabilized HIV trimers, the use of an array of sophisticated approaches for immunogen design, the development of novel animal models for immunogen evaluation and advanced technologies to interrogate antibody responses...
May 15, 2018: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29773829/sequential-immunizations-with-a-panel-of-hiv-1-env-virus-like-particles-coach-immune-system-to-make-broadly-neutralizing-antibodies
#3
Teena Mohan, Zachary Berman, Sang-Moo Kang, Bao-Zhong Wang
Broadly neutralizing antibodies (bnAbs) are correlated with passive HIV/SHIV protection and are desirable components of a HIV protective immunity. In the current study, we have designed a sequential-immunization strategy with a panel of envelope glycoprotein (Env)-enriched virus-like particles (VLPs) from various HIV-1 clades (A-E) to elicit bnAbs with high breadth and potency of neutralization in rabbits. We have compared this regimen with repetitive immunizations of individual Env (subtype B) VLPs or a mixture of various Env VLPs...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29768174/hiv-1-vaccines-based-on-antibody-identification-b-cell-ontogeny-and-epitope-structure
#4
REVIEW
Peter D Kwong, John R Mascola
HIV-1 vaccine development has been stymied by an inability to induce broadly reactive neutralizing antibodies to the envelope (Env) trimer, the sole viral antigen on the virion surface. Antibodies isolated from HIV-1-infected donors, however, have been shown to recognize all major exposed regions of the prefusion-closed Env trimer, and an emerging understanding of the immunological and structural characteristics of these antibodies and the epitopes they recognize is enabling new approaches to vaccine design...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29762173/a-defucosylated-bispecific-multivalent-molecule-exhibits-broad-hiv-1-neutralizing-activity-and-enhanced-adcc-against-reactivated-hiv-1-latently-infected-cells
#5
Desheng Kong, Yan Wang, Ping Ji, Wei Li, Tianlei Ying, Jinghe Huang, Chen Wang, Yanling Wu, Yanping Wang, Weizao Chen, Yanling Hao, Kunxue Hong, Yiming Shao, Dimiter S Dimitrov, Shibo Jiang, Liying Ma
OBJECTIVE: Current treatments cannot completely eradicate HIV-1 owing to the presence of latently infected cells which harbor transcriptionally silent HIV-1. However, defucosylated antibodies can readily kill latently infected cells after their activation to express envelope glycoprotein (Env) through antibody-dependent cellular cytotoxicity (ADCC). We herein aimed to test a defucosylated bispecific multivalent molecule consisting of domain-antibody and single-domain CD4, LSEVh-LS-F, for its HIV-1 neutralizing activity and ADCC against the reactivated latently infected cells, compared with the non-defucosylated molecule LSEVh-LS...
May 11, 2018: AIDS
https://www.readbyqxmd.com/read/29759530/emerging-glycobiology-tools-a-renaissance-in-accessibility
#6
REVIEW
Douglas M Oswald, Brian A Cobb
The glycobiology of the immune response is a topic that has garnered increased attention due to a number of key discoveries surrounding IgG function, the specificity of some broadly neutralizing anti-HIV antibodies, cancer immunoregulation by galectin molecules and others. This review is the opening article in a Special Edition of Cellular Immunology focused on glycoimmunology, and has the goal of setting the context for these articles by providing a mini-review of how glycans impact immunity. We also focus on some of the technological and methodological advances in the field of glycobiology that are being deployed to lower the barrier of entry into the glycosciences, and to more fully interrogate the glycome and its function...
April 25, 2018: Cellular Immunology
https://www.readbyqxmd.com/read/29746590/structural-and-immunologic-correlates-of-chemically-stabilized-hiv-1-envelope-glycoproteins
#7
Torben Schiffner, Jesper Pallesen, Rebecca A Russell, Jonathan Dodd, Natalia de Val, Celia C LaBranche, David Montefiori, Georgia D Tomaras, Xiaoying Shen, Scarlett L Harris, Amin E Moghaddam, Oleksandr Kalyuzhniy, Rogier W Sanders, Laura E McCoy, John P Moore, Andrew B Ward, Quentin J Sattentau
Inducing broad spectrum neutralizing antibodies against challenging pathogens such as HIV-1 is a major vaccine design goal, but may be hindered by conformational instability within viral envelope glycoproteins (Env). Chemical cross-linking is widely used for vaccine antigen stabilization, but how this process affects structure, antigenicity and immunogenicity is poorly understood and its use remains entirely empirical. We have solved the first cryo-EM structure of a cross-linked vaccine antigen. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a CD4 binding site-specific broadly neutralizing antibody (bNAb) Fab fragment reveals how cross-linking affects key properties of the trimer...
May 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29738673/top-down-chemoenzymatic-approach-to-synthesizing-diverse-high-mannose-n-glycans-and-related-neoglycoproteins-for-carbohydrate-microarray-analysis
#8
Christian Toonstra, Lisa Wu, Chao Li, Denong Wang, Lai-Xi Wang
High mannose type N-glycans are an important component of neutralizing epitopes on HIV-1 envelope glycoprotein gp120. They also serve as signals for protein folding, trafficking, and degradation in protein quality control. A number of lectins and antibodies recognize high-mannose type N-glycans, and glycan array technology has provided an avenue to probing these oligomannose-specific proteins. We describe in this paper a top-down chemoenzymatic approach to synthesizing a library of high-mannose N-glycans and related neoglycoproteins for glycan microarray analysis...
May 8, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29736600/investigation-of-sequence-clipping-and-structural-heterogeneity-of-an-hiv-broadly-neutralizing-antibody-by-a-comprehensive-lc-ms-analysis
#9
Vera B Ivleva, Nicole A Schneck, Deepika Gollapudi, Frank Arnold, Jonathan W Cooper, Q Paula Lei
CAP256 is one of the highly potent, broadly neutralizing monoclonal antibodies (bNAb) designed for HIV-1 therapy. During the process development of one of the constructs, an unexpected product-related impurity was observed via microfluidics gel electrophoresis. A panel of complementary LC-MS analyses was applied for the comprehensive characterization of CAP256 which included the analysis of the intact and reduced protein, the middle-up approach, and a set of complementary peptide mapping techniques and verification of the disulfide bonds...
May 7, 2018: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/29731169/identification-of-near-pan-neutralizing-antibodies-against-hiv-1-by-deconvolution-of-plasma-humoral-responses
#10
Mohammad Mohseni Sajadi, Amir Dashti, Zahra Rikhtegaran Tehrani, William D Tolbert, Michael S Seaman, Xin Ouyang, Neelakshi Gohain, Marzena Pazgier, Dongkyoon Kim, Guy Cavet, Jean Yared, Robert R Redfield, George K Lewis, Anthony L DeVico
Anti-HIV-1 envelope broadly neutralizing monoclonal antibodies (bNAbs) isolated from memory B cells may not fully represent HIV-1-neutralizing profiles measured in plasma. Accordingly, we characterized near-pan-neutralizing antibodies extracted directly from the plasma of two "elite neutralizers." Circulating anti-gp120 polyclonal antibodies were deconvoluted using proteomics to guide lineage analysis of bone marrow plasma cells. In both subjects, a single lineage of anti-CD4-binding site (CD4bs) antibodies explained the plasma-neutralizing activity...
April 28, 2018: Cell
https://www.readbyqxmd.com/read/29718999/glycoengineering-hiv-1-env-creates-supercharged-and-hybrid-glycans-to-increase-neutralizing-antibody-potency-breadth-and-saturation
#11
Ema T Crooks, Samantha L Grimley, Michelle Cully, Keiko Osawa, Gillian Dekkers, Kevin Saunders, Sebastian Rӓmisch, Sergey Menis, William R Schief, Nicole Doria-Rose, Barton Haynes, Ben Murrell, Evan Mitchel Cale, Amarendra Pegu, John R Mascola, Gestur Vidarsson, James M Binley
The extensive glycosylation of HIV-1 envelope (Env) glycoprotein leaves few glycan-free holes large enough to admit broadly neutralizing antibodies (bnAb). Consequently, most bnAbs must inevitably make some glycan contacts and avoid clashes with others. To investigate how Env glycan maturation regulates HIV sensitivity to bnAbs, we modified HIV-1 pseudovirus (PV) using various glycoengineering (GE) tools. Promoting the maturation of α-2,6 sialic acid (SA) glycan termini increased PV sensitivity to two bnAbs that target the V2 apex and one to the interface between Env surface gp120 and transmembrane gp41 subunits, typically by up to 30-fold...
May 2, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29697469/broadly-neutralizing-antibodies-for-treatment-and-prevention-of-hiv-1-infection
#12
Yehuda Z Cohen, Marina Caskey
PURPOSE OF REVIEW: Several anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency that target different HIV-1 envelope epitopes have been identified. bNAbs are an attractive new strategy for HIV-1 prevention and therapy, and potentially, for long-term remission or cure. Here, we discuss findings from early clinical studies that have evaluated these novel bNAbs. RECENT FINDINGS: Phase 1 studies of bNAbs targeting two distinct HIV-1 envelope epitopes have demonstrated their favorable safety and pharmacokinetic profile...
April 24, 2018: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/29689537/hiv-infection-advances-toward-a-cure
#13
Daniel C Douek
Achieving cure of HIV infection requires eliminating all replication-competent virus from the reservoir of latently infected cells or completely inhibiting infected cells from emerging from latency. Strategies include very early use of antiretroviral therapy; hematopoietic stem cell transplantation; "shock-and-kill" approaches; immune therapy with immune checkpoint inhibitors; gene therapy, including use of CC chemokine receptor 5-modified CD4+ T cells; and broadly neutralizing antibody therapy. Success is likely to require a combination of approaches...
April 2018: Topics in Antiviral Medicine
https://www.readbyqxmd.com/read/29689099/glycan-modifications-to-the-gp120-immunogens-used-in-the-rv144-vaccine-trial-improve-binding-to-broadly-neutralizing-antibodies
#14
Rachel C Doran, Gwen P Tatsuno, Sara M O'Rourke, Bin Yu, David L Alexander, Kathryn A Mesa, Phillip W Berman
To date, the RV144 HIV vaccine trial has been the only study to show that immunization can confer protection from HIV infection. While encouraging, the modest 31.2% (P = 0.04) efficacy achieved in this study left significant room for improvement, and created an incentive to optimize the AIDSVAX B/E vaccine immunogens to increase the level of vaccine efficacy. Since the completion of the RV144 trial, our understanding of the antigenic structure of the HIV envelope protein, gp120, and of the specificity of broadly neutralizing monoclonal antibodies (bN-mAbs) that bind to it, has significantly improved...
2018: PloS One
https://www.readbyqxmd.com/read/29683853/hiv-transmission-from-infected-cd4-t-cells-to-allogenic-t-and-dendritic-cells-is-inhibited-by-broadly-neutralizing-antibodies
#15
Camille Ducloy, Bin Su, Luzia Mayr, Jéromine Klingler, Thomas Decoville, Sylvie Schmidt, Géraldine Laumond, Nathalie Salomé, Seiamak Bahram, Christiane Moog
OBJECTIVE: In the semen, both free virus and infected cells are able to establish HIV infection during sexual intercourse. An efficient vaccine should, therefore, inhibit both infectious states. The aim of this study was to analyze the capacity of broadly neutralizing antibodies (bNAbs) to inhibit HIV transmission by the infected cells. DESIGN/METHODS: We developed an in-vitro model aiming to mimic mucosal HIV transmission via infected cells. PHA-activated CD4 T cells stained with PKH26 from donor A were infected and co-cultured with CD4 T cells and dendritic cells from donor B in the presence of bNAbs...
April 19, 2018: AIDS
https://www.readbyqxmd.com/read/29683434/tandem-bispecific-broadly-neutralizing-antibody-a-novel-approach-to-hiv-1-treatment
#16
Guido Ferrari
The last decade has led to a significant advance in our knowledge of HIV-1 latency and immunity. However, we are still not close to finding a cure for HIV-1. Although combination antiretroviral therapy (cART) has led to increased survival, almost close to that of the general population, it is still not curative. In the current issue of the JCI, Wu et al. studied the prophylactic and therapeutic potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb), BiIA-SG. This bnAb's breadth and potency were highly effective in protection and treatment settings, as measured by complete viremia control following direct infusion, as well as elimination of infected cells and delay in viral rebound when delivered with a recombinant vector...
April 23, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29677181/exploiting-glycan-topography-for-computational-design-of-env-glycoprotein-antigenicity
#17
Wen-Han Yu, Peng Zhao, Monia Draghi, Claudia Arevalo, Christina B Karsten, Todd J Suscovich, Bronwyn Gunn, Hendrik Streeck, Abraham L Brass, Michael Tiemeyer, Michael Seaman, John R Mascola, Lance Wells, Douglas A Lauffenburger, Galit Alter
Mounting evidence suggests that glycans, rather than merely serving as a "shield", contribute critically to antigenicity of the HIV envelope (Env) glycoprotein, representing critical antigenic determinants for many broadly neutralizing antibodies (bNAbs). While many studies have focused on defining the role of individual glycans or groups of proximal glycans in bNAb binding, little is known about the effects of changes in the overall glycan landscape in modulating antibody access and Env antigenicity...
April 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29672607/infant-transmitted-founder-hiv-1-viruses-from-peripartum-transmission-are-neutralization-resistant-to-paired-maternal-plasma
#18
Amit Kumar, Claire E P Smith, Elena E Giorgi, Joshua Eudailey, David R Martinez, Karina Yusim, Ayooluwa O Douglas, Lisa Stamper, Erin McGuire, Celia C LaBranche, David C Montefiori, Genevieve G Fouda, Feng Gao, Sallie R Permar
Despite extensive genetic diversity of HIV-1 in chronic infection, a single or few maternal virus variants become the founders of an infant's infection. These transmitted/founder (T/F) variants are of particular interest, as a maternal or infant HIV vaccine should raise envelope (Env) specific IgG responses capable of blocking this group of viruses. However, the maternal or infant factors that contribute to selection of infant T/F viruses are not well understood. In this study, we amplified HIV-1 env genes by single genome amplification from 16 mother-infant transmitting pairs from the U...
April 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29671786/hiv-vaccination-a-roadmap-among-advancements-and-concerns
#19
REVIEW
Maria Trovato, Luciana D'Apice, Antonella Prisco, Piergiuseppe De Berardinis
Since the identification of the Human Immunodeficiency Virus type 1 (HIV-1) as the etiologic agent of AIDS (Acquired Immunodeficiency Syndrome), many efforts have been made to stop the AIDS pandemic. A major success of medical research has been the development of the highly active antiretroviral therapy and its availability to an increasing number of people worldwide, with a considerable effect on survival. However, a safe and effective vaccine able to prevent and eradicate the HIV pandemic is still lacking...
April 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29669838/effects-of-adjuvants-on-hiv-1-envelope-glycoprotein-sosip-trimers-in-vitro
#20
Gabriel Ozorowski, Albert Cupo, Michael Golabek, Michelle LoPiccolo, Thomas A Ketas, Matt Cavallary, Christopher A Cottrell, P J Klasse, Andrew B Ward, John P Moore
Native-like, soluble, recombinant SOSIP trimers of various designs and based on several env genes of human immunodeficiency virus type 1 (HIV-1) are being tested as immunogens in different animal models. These experiments almost always involve co-formulating the trimers with an adjuvant to boost the magnitude of the immune responses. One factor relevant to the choice of an adjuvant is that it should not physically damage the immunogen or impede its ability to present relevant epitopes. As examples, an adjuvant formulation that includes harsh detergents could disrupt the structural integrity of a trimer, and any charged compounds in the formulation could bind to counter-charged regions of the trimer and physically occlude nearby epitopes...
April 18, 2018: Journal of Virology
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