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HIV neutralizing antibody

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https://www.readbyqxmd.com/read/29451984/two-component-ferritin-nanoparticles-for-multimerization-of-diverse-trimeric-antigens
#1
Ivelin S Georgiev, Michael Gordon Joyce, Rita E Chen, Kwanyee Leung, Krisha McKee, Aliaksandr Druz, Joseph G Van Galen, Masaru Kanekiyo, Yaroslav Tsybovsky, Eun Sung Yang, Yongping Yang, Priyamvada Acharya, Marie Pancera, Paul V Thomas, Timothy Wanninger, Hadi Yassine, Ulrich Baxa, Nicole Doria-Rose, Cheng Cheng, Barney S Graham, John R Mascola, Peter D Kwong
Antigen multimerization on a nanoparticle can result in improved neutralizing antibody responses. A platform that has been successfully used for displaying antigens from a number of different viruses is ferritin, a self-assembling protein nanoparticle that allows the attachment of multiple copies (twenty-four monomers or eight trimers) of a single antigen. Here we design two-component ferritin variants that allow the attachment of two diverse antigens on a single particle in a defined ratio and geometric pattern...
February 16, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29451898/integrating-linear-optimization-with-structural-modeling-to-increase-hiv-neutralization-breadth
#2
Alexander M Sevy, Swetasudha Panda, James E Crowe, Jens Meiler, Yevgeniy Vorobeychik
Computational protein design has been successful in modeling fixed backbone proteins in a single conformation. However, when modeling large ensembles of flexible proteins, current methods in protein design have been insufficient. Large barriers in the energy landscape are difficult to traverse while redesigning a protein sequence, and as a result current design methods only sample a fraction of available sequence space. We propose a new computational approach that combines traditional structure-based modeling using the Rosetta software suite with machine learning and integer linear programming to overcome limitations in the Rosetta sampling methods...
February 16, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29451475/-trispecific-broadly-neutralizing-antibodies-for-hiv-immunoprophylaxis-and-immunotherapy
#3
Francis Barin, Karl Stefic
No abstract text is available yet for this article.
February 2018: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/29449847/potential-epigenetic-regulation-in-the-germinal-center-reaction-of-lymphoid-tissues-in-hiv-siv-infection
#4
REVIEW
Xiaolei Wang, Huanbin Xu
The production of high-affinity and broadly neutralizing antibodies plays a key role in the defense against pathogens. These antibody responses require effective germinal center (GC) reaction within anatomical niches of GCs, where follicular helper T (Tfh) cells provide cognate help to B cells for T cell-dependent antibody responses. Emerging evidences indicate that GC reaction in normal state and perhaps establishment of latent Tfh cell reservoir in HIV/SIV infection are tightly regulated by epigenetic histone modifications, which are responsible for activating or silencing chromatin...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29449843/insights-into-the-structural-basis-of-antibody-affinity-maturation-from-next-generation-sequencing
#5
REVIEW
Arjun K Mishra, Roy A Mariuzza
Affinity maturation is the process whereby the immune system generates antibodies of higher affinities during a response to antigen. It is unique in being the only evolutionary mechanism known to operate on a molecule in an organism's own body. Deciphering the structural mechanisms through which somatic mutations in antibody genes increase affinity is critical to understanding the evolution of immune repertoires. Next-generation sequencing (NGS) has allowed the reconstruction of antibody clonal lineages in response to viral pathogens, such as HIV-1, which was not possible in earlier studies of affinity maturation...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29444432/surface-matrix-screening-identifies-semi-specific-interactions-that-improve-potency-of-a-near-pan-reactive-hiv-1-neutralizing-antibody
#6
Young D Kwon, Gwo-Yu Chuang, Baoshan Zhang, Robert T Bailer, Nicole A Doria-Rose, Tatyana S Gindin, Bob Lin, Mark K Louder, Krisha McKee, Sijy O'Dell, Amarendra Pegu, Stephen D Schmidt, Mangaiarkarasi Asokan, Xuejun Chen, Misook Choe, Ivelin S Georgiev, Vivian Jin, Marie Pancera, Reda Rawi, Keyun Wang, Rajoshi Chaudhuri, Lisa A Kueltzo, Slobodanka D Manceva, John-Paul Todd, Diana G Scorpio, Mikyung Kim, Ellis L Reinherz, Kshitij Wagh, Bette M Korber, Mark Connors, Lawrence Shapiro, John R Mascola, Peter D Kwong
Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29443078/chemo-enzymatic-synthesis-of-n-glycans-for-array-development-and-hiv-antibody-profiling
#7
Sachin S Shivatare, Vidya S Shivatare, Chung-Yi Wu, Chi-Huey Wong
We present a highly efficient way for the rapid preparation of a wide range of N-linked oligosaccharides (estimated to exceed 20,000 structures) that are commonly found on human glycoproteins. To achieve the desired structural diversity, the strategy began with the chemo-enzymatic synthesis of three kinds of oligosaccharyl fluoride modules, followed by their stepwise α-selective glycosylations at the 3-O and 6-O positions of the mannose residue of the common core trisaccharide having a crucial β-mannoside linkage...
February 5, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29442996/role-of-framework-mutations-and-antibody-flexibility-in-the-evolution-of-broadly-neutralizing-antibodies
#8
Victor Ovchinnikov, Joy E Louveau, John P Barton, Martin Karplus, Arup K Chakraborty
Eliciting antibodies that are cross reactive with surface proteins of diverse strains of highly mutable pathogens (e.g., HIV, influenza) could be key for developing effective universal vaccines. Mutations in the framework regions of such broadly neutralizing antibodies (bnAbs) have been reported to play a role in determining their properties. We used molecular dynamics simulations and models of affinity maturation to study specific bnAbs against HIV. Our results suggest specific classes of evolutionary lineages: if germline B cells that initiate affinity maturation have high affinity for the conserved residues of the targeted epitope, framework mutations increase antibody rigidity as affinity maturation progresses to evolve bnAbs...
February 14, 2018: ELife
https://www.readbyqxmd.com/read/29439644/potential-hiv-1-fusion-inhibitors-mimicking-gp41-specific-broadly-neutralizing-antibody-10e8-in-silico-discovery-and-prediction-of-antiviral-potency
#9
Alexander M Andrianov, Ivan A Kashyn, Alexander V Tuzikov
An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web-oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations...
January 15, 2018: Journal of Bioinformatics and Computational Biology
https://www.readbyqxmd.com/read/29437254/crispr-cas9-knockout-of-usp18-enhances-type-i-ifn-responsiveness-and-restricts-hiv-1-infection-in-macrophages
#10
Jared P Taylor, Melanie N Cash, Katherine E Santostefano, Mahito Nakanishi, Naohiro Terada, Mark A Wallet
The IFN-stimulated gene ubiquitin-specific proteinase 18 (USP18) encodes a protein that negatively regulates T1 IFN signaling via stearic inhibition of JAK1 recruitment to the IFN-α receptor 2 subunit (IFNAR2). Here, we demonstrate that USP18 expression is induced by HIV-1 in a T1 IFN-dependent manner. Experimental depletion of USP18 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing results in a significant restriction of HIV-1 replication in an induced pluripotent stem cell (iPSC)-derived macrophage model...
February 13, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29431588/aptamers-in-hiv-research-diagnosis-and-therapy
#11
Jyoti Bala, Srinivasan Chinnapaiyan, Rajib Kumar Dutta, Hoshang Unwalla
Aptamers are high affinity single-stranded nucleic acid or protein ligands which exhibit specificity and avidity comparable to, or exceeding that of antibodies and can be generated against most targets. The functionality of aptamers is based on their unique tertiary structure, complexity and their ability to attain unique binding pockets by folding. Aptamers are selected in vitro by a process called Systematic Evolution of Ligands by Exponential enrichment (SELEX). The Kd values for the selected aptamer are often in the picomolar to low nanomolar range...
February 12, 2018: RNA Biology
https://www.readbyqxmd.com/read/29429810/envelope-proteins-of-two-hiv-1-clades-induced-different-epitope-specific-antibody-response
#12
Tripti Shrivastava, Sweety Samal, Ashish K Tyagi, Sandeep Goswami, Naresh Kumar, Gabriel Ozorowski, Andrew B Ward, Bimal K Chakrabarti
Using HIV-1 envelope protein (Env)-based immunogens that closely mimic the conformation of functional HIV-1 Envs and represent the isolates prevalent in relevant geographical region is considered a rational approach towards developing HIV vaccine. We recently reported that like clade B Env, JRFL, membrane bound Indian clade C Env, 4-2.J41 is also efficiently cleaved and displays desirable antigenic properties for plasmid DNA immunization. Here, we evaluated the immune response in rabbit by injecting the animals with plasmid expressing membrane bound efficiently cleaved 4-2...
February 8, 2018: Vaccine
https://www.readbyqxmd.com/read/29422894/the-b-cell-follicle-in-hiv-infection-barrier-to-a-cure
#13
REVIEW
Matthew P Bronnimann, Pamela J Skinner, Elizabeth Connick
The majority of HIV replication occurs in secondary lymphoid organs (SLOs) such as the spleen, lymph nodes, and gut-associated lymphoid tissue. Within SLOs, HIV RNA+ cells are concentrated in the B-cell follicle during chronic untreated infection, and emerging data suggest that they are a major source of replication in treated disease as well. The concentration of HIV RNA+ cells in the B-cell follicle is mediated by several factors. Follicular CD4+ T-cell subsets including T-follicular helper cells and T-follicular regulatory cells are significantly more permissive to HIV than extrafollicular subsets...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29422056/turning-the-tables-on-cytomegalovirus-targeting-viral-fc-receptors-by-cars-containing-mutated-ch2-ch3-igg-spacer-domains
#14
Julia Proff, Charlotte U Brey, Armin Ensser, Wolfgang Holter, Manfred Lehner
BACKGROUND: During infection with human cytomegalovirus (HCMV) several viral proteins occur on cell surfaces in high quantity. We thus pursue an HLA-independent approach for immunotherapy of HCMV using chimeric antigen receptors (CARs) and bispecific BiTE® antibody constructs. In this context, HCMV-encoded proteins that mediate viral immune evasion and bind human IgG might represent particularly attractive target antigens. Unlike in observations of similar approaches for HIV and hepatitis B and C viruses, however, HCMV-infected cells develop a striking resistance to cytotoxic effector functions at later stages of the replication cycle...
February 8, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29420040/integrity-of-glycosylation-processing-of-a-glycan-depleted-trimeric-hiv-1-immunogen-targeting-key-b-cell-lineages
#15
Anna-Janina Behrens, Abhinav Kumar, Max Medina-Ramirez, Albert Cupo, Kevin Marshall, Victor M Cruz Portillo, David J Harvey, Gabriel Ozorowski, Nicole Zitzmann, Ian A Wilson, Andrew B Ward, Weston B Struwe, John P Moore, Rogier W Sanders, Max Crispin
Broadly neutralizing antibodies (bNAbs) that target the trimeric HIV-1 envelope glycoprotein spike (Env) are tools that can guide the design of recombinant Env proteins intended to engage the predicted human germline precursors of bNAbs (gl-bNAbs). The protein components of gl-bNAb epitopes are often masked by glycans, while mature bNAbs can evolve to accommodate or bypass these shielding glycans. The design of germline-targeting Env immunogens therefore includes the targeted deletion of specific glycan sites...
February 8, 2018: Journal of Proteome Research
https://www.readbyqxmd.com/read/29414440/induction-of-broadly-neutralizing-antibodies-in-germinal-centre-simulations
#16
REVIEW
Philippe A Robert, Andrea Lj Marschall, Michael Meyer-Hermann
Vaccines against mutating pathogens such as influenza, HIV, or plasmodium are poorly protective towards new evolving strains. Rare individuals naturally mount broadly neutralizing antibodies covering most strains, but the requirements for their induction are unknown. The antibody response to vaccination has been recapitulated by in silico models that proposed two opposite schemes: A theory of 'frustration' where one epitope at a time leads to optimal antibody breadth through sequential immunizations, that was proven successful for HIV vaccination in primates...
February 1, 2018: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/29386288/hiv-1-envelope-glycoproteins-from-diverse-clades-differentiate-antibody-responses-and-durability-among-vaccinees
#17
Nicole L Yates, Allan C deCamp, Bette T Korber, Hua-Xin Liao, Carmela Irene, Abraham Pinter, James Peacock, Linda J Harris, Sheetal Sawant, Peter Hraber, Xiaoying Shen, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Phillip W Berman, Merlin L Robb, Giuseppe Pantaleo, Susan Zolla-Pazner, Barton F Haynes, S Munir Alam, David C Montefiori, Georgia D Tomaras
Induction of broadly cross-reactive anti-viral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design. A major gap in the field is the identification of diverse HIV-1 envelope antigens to evaluate vaccine regimens for binding antibody breadth. In this study, we define unique antigen panels to map HIV-1 vaccine-elicited antibody breadth and durability. Diverse HIV-1 envelope glycoproteins were selected based on genetic and geographic diversity to cover the global epidemic, with a focus on sexually acquired transmitted/founder viruses with a tier-2 neutralization phenotype...
January 31, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29386285/functional-optimization-of-broadly-neutralizing-hiv-1-antibody-10e8-by-promoting-membrane-interactions
#18
Edurne Rujas, Daniel P Leaman, Sara Insausti, Lei Ortigosa-Pascual, Lei Zhang, Michael B Zwick, José L Nieva
The 10E8 antibody targets a helical epitope in the membrane-proximal external region (MPER) and transmembrane domain (TMD) of the envelope glycoprotein (Env) subunit gp41, and is among the broadest known neutralizing antibodies against HIV-1. Accordingly, this antibody and its mechanism of action valuably inform the design of effective vaccines and immunotherapies. 10E8 exhibits unusual adaptations to attain specific, high-affinity binding to the MPER at the viral membrane interface. Reversing charge of the basic paratope surface (from net positive to net negative) reportedly lowered its neutralization potency...
January 31, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29386130/elicitation-of-neutralizing-antibodies-targeting-the-v2-apex-of-the-hiv-envelope-trimer-in-a-wild-type-animal-model
#19
James E Voss, Raiees Andrabi, Laura E McCoy, Natalia de Val, Roberta P Fuller, Terrence Messmer, Ching-Yao Su, Devin Sok, Salar N Khan, Fernando Garces, Laura K Pritchard, Richard T Wyatt, Andrew B Ward, Max Crispin, Ian A Wilson, Dennis R Burton
No abstract text is available yet for this article.
January 23, 2018: Cell Reports
https://www.readbyqxmd.com/read/29370305/alterations-of-hiv-1-envelope-phenotype-and-antibody-mediated-neutralization-by-signal-peptide-mutations
#20
Chitra Upadhyay, Roya Feyznezhad, Weiming Yang, Hui Zhang, Susan Zolla-Pazner, Catarina E Hioe
HIV-1 envelope glycoprotein (Env) mediates virus attachment and entry into the host cells. Like other membrane-bound and secreted proteins, HIV-1 Env contains at its N terminus a signal peptide (SP) that directs the nascent Env to the endoplasmic reticulum (ER) where Env synthesis and post-translational modifications take place. SP is cleaved during Env biosynthesis but potentially influences the phenotypic traits of the Env protein. The Env SP sequences of HIV-1 isolates display high sequence variability, and the significance of such variability is unclear...
January 25, 2018: PLoS Pathogens
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