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Hiv and broadly neutralizing antibody

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https://www.readbyqxmd.com/read/28747530/sequence-intrinsic-somatic-mutation-mechanisms-contribute-to-affinity-maturation-of-vrc01-class-hiv-1-broadly-neutralizing-antibodies
#1
Joyce K Hwang, Chong Wang, Zhou Du, Robin M Meyers, Thomas B Kepler, Donna Neuberg, Peter D Kwong, John R Mascola, M Gordon Joyce, Mattia Bonsignori, Barton F Haynes, Leng-Siew Yeap, Frederick W Alt
Variable regions of Ig chains provide the antigen recognition portion of B-cell receptors and derivative antibodies. Ig heavy-chain variable region exons are assembled developmentally from V, D, J gene segments. Each variable region contains three antigen-contacting complementarity-determining regions (CDRs), with CDR1 and CDR2 encoded by the V segment and CDR3 encoded by the V(D)J junction region. Antigen-stimulated germinal center (GC) B cells undergo somatic hypermutation (SHM) of V(D)J exons followed by selection for SHMs that increase antigen-binding affinity...
July 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28747500/panels-of-hiv-1-subtype-c-env-reference-strains-for-standardized-neutralization-assessments
#2
Peter Hraber, Cecilia Rademeyer, Carolyn Williamson, Michael S Seaman, Raphael Gottardo, Haili Tang, Kelli Greene, Hongmei Gao, Celia LaBranche, John R Mascola, Lynn Morris, David C Montefiori, Bette Korber
In the search for effective immunologic interventions to prevent and treat HIV-1 infection, standardized reference reagents are a cost-effective way to maintain robustness and reproducibility among immunological assays. To support planned and ongoing studies where clade C predominates, here we describe three virus panels, chosen from 200 well-characterized clade C envelope (Env)-pseudotyped viruses from early infection. All 200 Envs were expressed as single-round of replication pseudoviruses, and tested to quantify neutralization titers by 16 broadly neutralizing antibodies (bnAbs) and sera from 30 subjects with chronic clade C infections...
July 26, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28743743/characterization-of-a-stable-hiv-1-b-c-recombinant-soluble-and-trimeric-envelope-glycoprotein-env-highly-resistant-to-cd4-induced-conformational-changes
#3
Rajesh Kumar, Gabriel Ozorowski, Vivek Kumar, Lauren G Holden, Tripti Shrivastava, Shilpa Patil, Suprit Deshpande, Andrew B Ward, Jayanta Bhattacharya
The HIV-1 envelope (Env) is a glycoprotein which is a trimer of heterodimer containing gp120 and gp41 subunits, mediates virus entry and is a major target of broadly neutralizing antibodies (bnAbs) developed during infection in some individuals. The engagement of the HIV-1 gp120 glycoprotein to the host CD4 protein triggers conformational changes in gp120 that allows its binding to coreceptors, and is necessary for virus entry to establish infection. Native-like HIV-1 Env immunogens representing distinct clades have been proposed to improve immunogenicity of bnAbs...
July 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28740221/escape-from-humoral-immunity-is-associated-with-treatment-failure-in-hiv-1-infected-patients-receiving-long-term-antiretroviral-therapy
#4
Yabo Ouyang, Qianqian Yin, Wei Li, Zhenpeng Li, Desheng Kong, Yanling Wu, Kunxue Hong, Hui Xing, Yiming Shao, Shibo Jiang, Tianlei Ying, Liying Ma
Interindividual heterogeneity in the disease progression of HIV-1-infected patients receiving long-term antiretroviral therapy suggests that some host-related factors may have limited treatment efficacy. To understand the nature of factors contributing to treatment failure, we performed a retrospective cohort study of 45 chronically HIV-1-infected individuals sharing a similar demographics and route of infection, compared the differences between virologically suppressed (VS) and treatment failure (TF) patients with respect to clinical, immunological and virological characteristics...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28738289/germinal-center-enhancement-by-extended-antigen-availability
#5
REVIEW
Kimberly M Cirelli, Shane Crotty
Vaccine elicitation of protective antibody responses has proved difficult for a number of important human pathogens, including HIV-1. The amount of somatic hypermutation associated with the development of broadly neutralizing antibodies against HIV has not been achieved using conventional immunization strategies. An underexplored aspect of vaccine design is modulation of antigen kinetics. Immunization strategies with extended antigen availability have recently been shown to enhance humoral responses. In this review, we explore the mechanisms through which sustained antigen availability can enhance germinal center responses and the potency of antibody responses...
July 21, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28732199/catch-shiny-droplets-in-suspension-finding-the-needle-in-a-haystack
#6
Nina V Hein-Fuchs, Renate König
In a recent issue of Cell Chemical Biology, Chaipan et al. (2017) described a high-throughput screening methodology to identify epitopes on HIV-1 particles recognized by broadly neutralizing antibodies. The approach utilizes a droplet-based microfluidics platform combining robust phenotypic single-virus sorting with next-generation sequencing of viral quasispecies.
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28728075/immunological-tolerance-as-a-barrier-to-protective-hiv-humoral-immunity
#7
REVIEW
Kristin Ms Schroeder, Amanda Agazio, Raul M Torres
HIV-1 infection typically eludes antibody control by our immune system and is not yet prevented by a vaccine. While many viral features contribute to this immune evasion, broadly neutralizing antibodies (bnAbs) against HIV-1 are often autoreactive and it has been suggested that immunological tolerance may restrict a neutralizing antibody response. Indeed, recent Ig knockin mouse studies have shown that bnAb-expressing B cells are largely censored by central tolerance in the bone marrow. However, the contribution of peripheral tolerance in limiting the HIV antibody response by anergic and potentially protective B cells is poorly understood...
July 17, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28726771/rapid-elicitation-of-broadly-neutralizing-antibodies-to-hiv-by-immunization-in-cows
#8
Devin Sok, Khoa M Le, Melissa Vadnais, Karen Saye-Francisco, Joseph G Jardine, Jonathan Torres, Zachary T Berndsen, Leopold Kong, Robyn Stanfield, Jennifer Ruiz, Alejandra Ramos, Chi-Hui Liang, Patricia L Chen, Michael F Criscitiello, Waithaka Mwangi, Ian A Wilson, Andrew B Ward, Vaughn V Smider, Dennis R Burton
No immunogen to date has reliably elicited broadly neutralizing antibodies to HIV in humans or animal models. Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env)(1) have improved the elicitation of potent isolate-specific antibody responses in rabbits(2) and macaques(3), but so far failed to induce broadly neutralizing antibodies. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes...
July 20, 2017: Nature
https://www.readbyqxmd.com/read/28700571/open-and-closed-structures-reveal-allostery-and-pliability-in-the-hiv-1-envelope-spike
#9
Gabriel Ozorowski, Jesper Pallesen, Natalia de Val, Dmitry Lyumkis, Christopher A Cottrell, Jonathan L Torres, Jeffrey Copps, Robyn L Stanfield, Albert Cupo, Pavel Pugach, John P Moore, Ian A Wilson, Andrew B Ward
For many enveloped viruses, binding to a receptor(s) on a host cell acts as the first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion. Although Env can tolerate a high degree of mutation in five variable regions (V1-V5), and also at N-linked glycosylation sites that contribute roughly half the mass of Env, the functional sites for recognition of receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral fitness...
July 12, 2017: Nature
https://www.readbyqxmd.com/read/28698284/breaching-peripheral-tolerance-promotes-the-production-of-hiv-1-neutralizing-antibodies
#10
Kristin M S Schroeder, Amanda Agazio, Pamela J Strauch, Sean T Jones, Scott B Thompson, Michael S Harper, Roberta Pelanda, Mario L Santiago, Raul M Torres
A subset of characterized HIV-1 broadly neutralizing antibodies (bnAbs) are polyreactive with additional specificities for self-antigens and it has been proposed immunological tolerance may present a barrier to their participation in protective humoral immunity. We address this hypothesis by immunizing autoimmune-prone mice with HIV-1 Envelope (Env) and characterizing the primary antibody response for HIV-1 neutralization. We find autoimmune mice generate neutralizing antibody responses to tier 2 HIV-1 strains with alum treatment alone in the absence of Env...
July 11, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28696188/evolution-of-cross-neutralizing-antibodies-and-mapping-epitope-specificity-in-plasma-of-chronic-hiv-1-infected-antiretroviral-therapy-na%C3%A3-ve-children-from-india
#11
Muzamil A Makhdoomi, Lubina Khan, Sanjeev Kumar, Heena Aggarwal, Ravinder Singh, Rakesh Lodha, Mohit Singla, Bimal K Das, Sushil K Kabra, Kalpana Luthra
Delineating the factors leading to the development of broadly neutralizing antibodies (bnAbs) during natural HIV-1 infection and dissecting their epitope specificities generates useful information for vaccine design. This is the first longitudinal study to assess the plasma-neutralizing antibody response and neutralizing determinants in HIV-1-infected children from India. We enrolled 26 and followed up 20 antiretroviral therapy (ART)-naïve, asymptomatic, chronic HIV-1-infected children. Five (19.2 %) baseline and 10 (50 %) follow-up plasma samples neutralized ≥50 % of subtypes A, B and C tier 2 viruses at an ID50 titre ≥150...
July 12, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28696158/immunization-with-hiv-1-envelope-t20-encoding-dna-vaccines-elicits-cross-clade-neutralizing-antibody-responses
#12
S Stenler, K E Lundin, L Hansen, S Petkov, N Mozafari, M Isaguliants, P Blomberg, C I E Smith, D M Goldenberg, C-H Chang, K Ljungberg, J Hinkula, B Wahren
BACKGROUND: Genetic immunization is expected to induce the expression of antigens in a native form. The encoded peptide epitopes are presented on endogenous MHC molecules, mimicking antigen presentation during a viral infection. We have explored the potential of enfuvirtide (T20), a short HIV peptide with antiviral properties, to enhance immune response to HIV antigens. To generate an expression vector, the T20 sequence was cloned into a conventional plasmid, the novel minicircle construct, and a replicon plasmid...
July 11, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28679760/co-operation-between-strain-specific-and-broadly-neutralizing-responses-limited-viral-escape-and-prolonged-exposure-of-the-broadly-neutralizing-epitope
#13
Colin Anthony, Talita York, Valerie Bekker, David Matten, Philippe Selhorst, Roux-Cil Ferreria, Nigel J Garrett, Salim S Abdool Karim, Lynn Morris, Natasha T Wood, Penny L Moore, Carolyn Williamson
V3-glycan targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan directed bNAbs, compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly, via a N334 to N332 glycan switch, which took just 7...
July 5, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28667249/conformational-heterogeneity-of-the-hiv-envelope-glycan-shield
#14
Mingjun Yang, Jing Huang, Raphael Simon, Lai-Xi Wang, Alexander D MacKerell
To better understand the conformational properties of the glycan shield covering the surface of the HIV gp120/gp41 envelope (Env) trimer, and how the glycan shield impacts the accessibility of the underlying protein surface, we performed enhanced sampling molecular dynamics (MD) simulations of a model glycosylated HIV Env protein and related systems. Our simulation studies revealed a conformationally heterogeneous glycan shield with a network of glycan-glycan interactions more extensive than those observed to date...
June 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28658672/identification-of-a-novel-hiv-1-neutralizing-antibody-from-a-crf07_bc-infected-chinese-donor
#15
Youxiang Sun, Yuanyuan Qiao, Yuanmei Zhu, Huihui Chong, Yuxian He
The identification of human monoclonal antibodies (mAbs) able to neutralize a broad spectrum of primary HIV-1 isolates is highly important for understanding the immune response of HIV-1 infection and developing vaccines and therapeutics. In this study, we isolated a novel human mAb termed Y498 from a phage display antibody library constructed with the PBMC samples of a CRF07_BC-infected Chinese donor whose sera exhibited broadly neutralizing activity. Y498 cross-reacted with diverse Env antigens and neutralized 30% of 70 tested HIV-1 isolates...
June 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28651892/construction-of-a-recombinant-full-length-membrane-associated-igg-library
#16
Zehua Sun, Shiqiang Lu, Zheng Yang, Jingjing Li, Mei-Yun Zhang
HIV/AIDS has become a global pandemic. Development of an effective HIV-1 vaccine eliciting broadly neutralizing monoclonal antibodies (bnmAbs) remains a big challenge. Before an effective vaccine comes out, passive treatment for prevention and protection of HIV-1 infection may alleviate the burden caused by the pandemic. Numerous bnmAbs have been isolated against different epitopes in HIV-1 envelope glycoprotein via phage/yeast display, EBV-immortalization, single cell sorting and micro neutralization. Recombinant antibody library with extended diversity and enlarged size of units are applicable by phage/yeast display and mammalian cell display for monoclonal antibody isolation...
June 24, 2017: Virus Research
https://www.readbyqxmd.com/read/28645240/engineered-expression-of-broadly-neutralizing-antibodies-against-human-immunodeficiency-virus
#17
Maham Ahmad, Osama M Ahmed, Bruce Schnepp, Philip R Johnson
This review discusses recent progress made in developing a vaccine and novel treatments for human immunodeficiency virus (HIV). It highlights the shortcomings of the RV144 vaccination trial [ALVAC-HIV (vCP1521) and AIDSVAX B/E] and the current standard of care and proposes that engineered expression of broadly neutralizing antibodies (bNAbs) against HIV-1 could overcome these shortcomings. Current developments in three major lines of research on HIV prevention and treatment using bNAbs are reviewed: firstly, the use of sequential immunogens to activate B cells to express bNAbs; secondly, the delivery of novel and extremely potent bNAbs through passive administration; and finally, the use of gene transfer using adeno-associated viral vectors to deliver bNAbs...
June 23, 2017: Annual Review of Virology
https://www.readbyqxmd.com/read/28632942/the-glycans-mediated-mechanism-on-the-interactions-of-gp120-with-cd4-and-antibody-insights-from-molecular-dynamics-simulation
#18
Yan Zhang, Yuzhen Niu, Jia Qi Tian, Xuewei Liu, Xiaojun Yao, Huanxiang Liu
N-linked glycans such as 234 and 276 gp120 glycans are vital components of HIV evasion from humoral immunity and important for HIV-1 neutralization of many broadly neutralizing antibodies (bNAbs). However, it is unknown the action mechanism of two glycans. To investigate the roles of the glycans on the interactions of gp120 with CD4 and antibody, molecular dynamics simulations based on gp120-CD4-8ANC195 complex with 234 and 276 gp120 glycans, 234 gp120 glycan, 276 gp120 glycan and without glycan were performed...
June 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28630079/what-are-the-primary-limitations-in-b-cell-affinity-maturation-and-how-much-affinity-maturation-can-we-drive-with-vaccination-lessons-from-the-antibody-response-to-hiv-1
#19
Gabriel D Victora, Hugo Mouquet
Most broadly neutralizing antibodies to HIV-1 have in common an extreme degree of somatic hypermutation (SHM), which correlates with their ability to neutralize multiple viral strains. However, achieving such extreme SHM by immunization remains a challenge. Here, we discuss how antigenic variation during HIV-1 infection may work to exacerbate SHM by permitting multiple iterative cycles of affinity maturation in germinal centers, and speculate on how this could be recapitulated through vaccination.
June 19, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28630077/what-are-the-primary-limitations-in-b-cell-affinity-maturation-and-how-much-affinity-maturation-can-we-drive-with-vaccination-breaking-through-immunity-s-glass-ceiling
#20
Garnett Kelsoe, Barton F Haynes
A key goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs) targeted to the vulnerable regions of the HIV envelope. BnAbs develop over time in ∼50% of HIV-1-infected individuals. However, to date, no vaccines have induced bnAbs and few or none of these vaccine-elicited HIV-1 antibodies carry the high frequencies of V(D)J mutations characteristic of bnAbs. Do the high frequencies of mutations characteristic of naturally induced bnAbs represent a fundamental barrier to the induction of bnAbs by vaccines? Recent studies suggest that high frequencies of V(D)J mutations can be achieved by serial vaccination strategies...
June 19, 2017: Cold Spring Harbor Perspectives in Biology
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