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Hiv and broadly neutralizing antibody

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https://www.readbyqxmd.com/read/28300601/functional-contacts-between-mper-and-the-anti-hiv-1-broadly-neutralizing-antibody-4e10-extend-into-the-core-of-the-membrane
#1
Edurne Rujas, Sara Insausti, Miguel García-Porras, Rubén Sánchez-Eugenia, Kouhei Tsumoto, José L Nieva, Jose M M Caaveiro
The exceptional breadth of broadly neutralizing antibodies (bNAbs) against the membrane-proximal external region (MPER) of the transmembrane protein gp41 makes this class of antibodies an ideal model to design HIV vaccines. From a practical point of view, however, the preparation of vaccines eliciting bNAbs is still a major roadblock that limits their clinical application. Fresh mechanistic insights are necessary to develop more effective strategies. In particular, the function of the unusually long complementary determining region three of the heavy chain (CDRH3) of 4E10, an anti-MPER bNAb, is an open question that fascinates researchers in the field...
March 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28298421/mimicry-of-an-hiv-broadly-neutralizing-antibody-epitope-with-a-synthetic-glycopeptide
#2
S Munir Alam, Baptiste Aussedat, Yusuf Vohra, R Ryan Meyerhoff, Evan M Cale, William E Walkowicz, Nathan A Radakovich, Kara Anasti, Lawrence Armand, Robert Parks, Laura Sutherland, Richard Scearce, M Gordon Joyce, Marie Pancera, Aliaksandr Druz, Ivelin S Georgiev, Tarra Von Holle, Amanda Eaton, Christopher Fox, Steven G Reed, Mark Louder, Robert T Bailer, Lynn Morris, Salim S Abdool-Karim, Myron Cohen, Hua-Xin Liao, David C Montefiori, Peter K Park, Alberto Fernández-Tejada, Kevin Wiehe, Sampa Santra, Thomas B Kepler, Kevin O Saunders, Joseph Sodroski, Peter D Kwong, John R Mascola, Mattia Bonsignori, M Anthony Moody, Samuel Danishefsky, Barton F Haynes
A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man9-V3). V3-glycan bnAbs bound to Man9-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man9-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual...
March 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28298420/staged-induction-of-hiv-1-glycan-dependent-broadly-neutralizing-antibodies
#3
Mattia Bonsignori, Edward F Kreider, Daniela Fera, R Ryan Meyerhoff, Todd Bradley, Kevin Wiehe, S Munir Alam, Baptiste Aussedat, William E Walkowicz, Kwan-Ki Hwang, Kevin O Saunders, Ruijun Zhang, Morgan A Gladden, Anthony Monroe, Amit Kumar, Shi-Mao Xia, Melissa Cooper, Mark K Louder, Krisha McKee, Robert T Bailer, Brendan W Pier, Claudia A Jette, Garnett Kelsoe, Wilton B Williams, Lynn Morris, John Kappes, Kshitij Wagh, Gift Kamanga, Myron S Cohen, Peter T Hraber, David C Montefiori, Ashley Trama, Hua-Xin Liao, Thomas B Kepler, M Anthony Moody, Feng Gao, Samuel J Danishefsky, John R Mascola, George M Shaw, Beatrice H Hahn, Stephen C Harrison, Bette T Korber, Barton F Haynes
A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb...
March 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28289286/early-antibody-therapy-can-induce-long-lasting-immunity-to-shiv
#4
Yoshiaki Nishimura, Rajeev Gautam, Tae-Wook Chun, Reza Sadjadpour, Kathryn E Foulds, Masashi Shingai, Florian Klein, Anna Gazumyan, Jovana Golijanin, Mitzi Donaldson, Olivia K Donau, Ronald J Plishka, Alicia Buckler-White, Michael S Seaman, Jeffrey D Lifson, Richard A Koup, Anthony S Fauci, Michel C Nussenzweig, Malcolm A Martin
Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control...
March 13, 2017: Nature
https://www.readbyqxmd.com/read/28284876/dual-immunity-concomitantly-suppresses-hiv-1-progression
#5
Huma Qureshi, Jayanta Bhattacharya
Broadly neutralizing antibodies (bnAbs) elicited in HIV-1(+) elite neutralizers typically are unable to reduce viremia in the same individuals from whom they are isolated. A recent study reports the development of bnAbs in an elite controller that, along with the help of T cells, were associated with restricting HIV-1 progression.
March 8, 2017: Trends in Microbiology
https://www.readbyqxmd.com/read/28283570/stabilization-of-a-soluble-native-like-trimeric-form-of-an-efficiently-cleaved-indian-hiv-1-clade-c-envelope-glycoprotein
#6
Shubbir Ahmed, Tripti Shrivastava, Naresh Kumar, Gabriel Ozorowski, Andrew B Ward, Bimal K Chakrabarti
Designing an effective HIV-1 envelope glycoprotein (Env) immunogen for elicitation of broadly neutralizing antibodies (bNAbs) is a challenging task owing to the high sequence diversity, heavy glycosylation and inherent meta-stability of Env. Based on the antigenic profile of recently isolated bNAbs, the rational approach to immunogen design is to make a stable version of the Env trimer, which mimics the native trimeric Env present on the viral surface. The SOSIP.664 form of a clade A Env, BG505, yields a homogeneous and well-ordered pre-fusion trimeric form, which maintains structural integrity and desired antigenicity...
March 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28281871/progress-in-hiv-vaccine-development
#7
Denise C Hsu, Robert J O'Connell
An HIV-1 vaccine is needed to curtail the HIV epidemic. Only one (RV144) out of the 6 HIV-1 vaccine efficacy trials performed showed efficacy. A potential mechanism of protection is the induction of functional antibodies to V1V2 region of HIV envelope. The 2 main current approaches to the generation of protective immunity are through broadly neutralizing antibodies (bnAb) and induction of functional antibodies (non-neutralizing Abs with other potential anti-viral functions). Passive immunization using bnAb has advanced into phase II clinical trials...
March 10, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28275193/structure-based-design-of-a-soluble-prefusion-closed-hiv-1-env-trimer-with-reduced-cd4-affinity-and-improved-immunogenicity
#8
Gwo-Yu Chuang, Hui Geng, Marie Pancera, Kai Xu, Cheng Cheng, Priyamvada Acharya, Michael Chambers, Aliaksandr Druz, Yaroslav Tsybovsky, Timothy G Wanninger, Yongping Yang, Nicole A Doria-Rose, Ivelin S Georgiev, Jason Gorman, M Gordon Joyce, Sijy O'Dell, Tongqing Zhou, Adrian B McDermott, John R Mascola, Peter D Kwong
The HIV-1-envelope (Env) trimer is a target for vaccine design as well as a conformational machine that facilitates virus entry by transitioning between prefusion-closed, CD4-bound, and co-receptor-bound conformations before rearranging into a postfusion state. Vaccine designers have sought to restrict the conformation of the HIV-1-Env trimer to its prefusion-closed state, as this state is recognized by most broadly neutralizing -but not by non-neutralizing- antibodies. We previously identified a disulfide bond, I201C-A433C (DS), which stabilizes Env in the vaccine-desired prefusion-closed state...
March 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28257303/effective-hiv-vaccine-narrow-path-to-broadly-neutralizing-antibodies
#9
Ralf Wagner
No abstract text is available yet for this article.
March 10, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28257302/progress-in-hiv-1-antibody-research-using-humanized-mice
#10
Henning Gruell, Florian Klein
PURPOSE OF REVIEW: Recent discoveries of highly potent broadly HIV-1 neutralizing antibodies provide new opportunities to successfully prevent, treat, and potentially cure HIV-1 infection. To test their activity in vivo, humanized mice have been shown to be a powerful model and were used to investigate antibody-mediated prevention and therapy approaches. In this review, we will summarize recent findings in humanized mice that have informed on the potential use of broadly neutralizing antibodies targeting HIV-1 in humans...
March 2, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28257301/adjuvants-tailoring-humoral-immune-responses
#11
M Juliana McElrath
PURPOSE OF REVIEW: The development and availability of new-generation adjuvants beyond aluminum and emulsion formulations, together with a deeper understanding of the mechanistic role of adjuvant formulations in stimulating innate immunity and offer opportunities to improve candidate vaccine designs intended to protect against HIV-1 acquisition. RECENT FINDINGS: Currently, major efforts in vaccine development focus on improving prime-boost vaccine regimens to enhance efficacy beyond 31% observed in the RV144 phase 3 study and to develop a pathway to induce broadly reactive HIV neutralizing antibodies...
March 2, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28257300/guiding-the-long-way-to-broad-hiv-neutralization
#12
David Peterhoff, Ralf Wagner
PURPOSE OF REVIEW: It has been demonstrated that extensive virus diversification and antibody coevolution are necessary to give rise to broadly neutralizing antibodies targeting the envelope protein of HIV-1. Here, we discuss recent progress of vaccine design approaches aiming on strategies to initiate and guide B-cell development toward this outcome, as well as their evaluation in mouse models engineered to express human antibodies. RECENT FINDINGS: Several specially tailored transgenic mouse strains have been developed to test the concept of engaging and guiding B-cell development by sequential immunizations...
March 2, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28251988/administration-of-nucleoside-modified-mrna-encoding-broadly-neutralizing-antibody-protects-humanized-mice-from-hiv-1-challenge
#13
Norbert Pardi, Anthony J Secreto, Xiaochuan Shan, Fotini Debonera, Joshua Glover, Yanjie Yi, Hiromi Muramatsu, Houping Ni, Barbara L Mui, Ying K Tam, Farida Shaheen, Ronald G Collman, Katalin Karikó, Gwenn A Danet-Desnoyers, Thomas D Madden, Michael J Hope, Drew Weissman
Monoclonal antibodies are one of the fastest growing classes of pharmaceutical products, however, their potential is limited by the high cost of development and manufacturing. Here we present a safe and cost-effective platform for in vivo expression of therapeutic antibodies using nucleoside-modified mRNA. To demonstrate feasibility and protective efficacy, nucleoside-modified mRNAs encoding the light and heavy chains of the broadly neutralizing anti-HIV-1 antibody VRC01 are generated and encapsulated into lipid nanoparticles...
March 2, 2017: Nature Communications
https://www.readbyqxmd.com/read/28250119/new-connections-cell-to-cell-hiv-1-transmission-resistance-to-broadly-neutralizing-antibodies-and-an-envelope-sorting-motif
#14
S Abigail Smith, Cynthia A Derdeyn
HIV-1 infection from cell to cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al show that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell to cell infection in a context dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28249163/vaccine-elicitation-of-high-mannose-dependent-neutralizing-antibodies-against-the-v3-glycan-broadly-neutralizing-epitope-in-nonhuman-primates
#15
Kevin O Saunders, Nathan I Nicely, Kevin Wiehe, Mattia Bonsignori, R Ryan Meyerhoff, Robert Parks, William E Walkowicz, Baptiste Aussedat, Nelson R Wu, Fangping Cai, Yusuf Vohra, Peter K Park, Amanda Eaton, Eden P Go, Laura L Sutherland, Richard M Scearce, Dan H Barouch, Ruijun Zhang, Tarra Von Holle, R Glenn Overman, Kara Anasti, Rogier W Sanders, M Anthony Moody, Thomas B Kepler, Bette Korber, Heather Desaire, Sampa Santra, Norman L Letvin, Gary J Nabel, David C Montefiori, Georgia D Tomaras, Hua-Xin Liao, S Munir Alam, Samuel J Danishefsky, Barton F Haynes
Induction of broadly neutralizing antibodies (bnAbs) that target HIV-1 envelope (Env) is a goal of HIV-1 vaccine development. A bnAb target is the Env third variable loop (V3)-glycan site. To determine whether immunization could induce antibodies to the V3-glycan bnAb binding site, we repetitively immunized macaques over a 4-year period with an Env expressing V3-high mannose glycans. Env immunizations elicited plasma antibodies that neutralized HIV-1 expressing only high-mannose glycans-a characteristic shared by early bnAb B cell lineage members...
February 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/28246356/differential-antibody-responses-to-conserved-hiv-1-neutralizing-epitopes-in-the-context-of-multivalent-scaffolds-and-native-like-gp140-trimers
#16
Charles D Morris, Parisa Azadnia, Natalia de Val, Nemil Vora, Andrew Honda, Erick Giang, Karen Saye-Francisco, Yushao Cheng, Xiaohe Lin, Colin J Mann, Jeffrey Tang, Devin Sok, Dennis R Burton, Mansun Law, Andrew B Ward, Linling He, Jiang Zhu
Broadly neutralizing antibodies (bNAbs) have provided valuable insights into the humoral immune response to HIV-1. While rationally designed epitope scaffolds and well-folded gp140 trimers have been proposed as vaccine antigens, a comparative understanding of their antibody responses has not yet been established. In this study, we probed antibody responses to the N332 supersite and the membrane-proximal external region (MPER) in the context of heterologous protein scaffolds and native-like gp140 trimers. Ferritin nanoparticles and fragment crystallizable (Fc) regions were utilized as multivalent carriers to display scaffold antigens with grafted N332 and MPER epitopes, respectively...
February 28, 2017: MBio
https://www.readbyqxmd.com/read/28239654/flow-virometric-sorting-and-analysis-of-hiv-quasispecies-from-plasma
#17
Thomas Musich, Jennifer C Jones, Brandon F Keele, Lisa M Miller Jenkins, Thorsten Demberg, Thomas S Uldrick, Robert Yarchoan, Marjorie Robert-Guroff
Flow cytometry is utilized extensively for cellular analysis, but technical limitations have prevented its routine application for characterizing virus. The recent introduction of nanoscale fluorescence-activated cytometric cell sorting now allows analysis of individual virions. Here, we demonstrate staining and sorting of infectious HIV. Fluorescent antibodies specific for cellular molecules found on budding virions were used to label CCR5-tropic Bal HIV and CXCR4-tropic NL4.3 HIV Env-expressing pseudovirions made in THP-1 cells (monocyte/macrophage) and H9 cells (T cells), respectively...
February 23, 2017: JCI Insight
https://www.readbyqxmd.com/read/28237764/evaluation-of-a-novel-multi-immunogen-vaccine-strategy-for-targeting-4e10-10e8-neutralizing-epitopes-on-hiv-1-gp41-membrane-proximal-external-region
#18
Saikat Banerjee, Heliang Shi, Marisa Banasik, Hojin Moon, William Lees, Yali Qin, Andrew Harley, Adrian Shepherd, Michael W Cho
The membrane proximal external region (MPER) of HIV-1 gp41 is targeted by broadly neutralizing antibodies (bnAbs) 4E10 and 10E8. In this proof-of-concept study, we evaluated a novel multi-immunogen vaccine strategy referred to as Incremental, Phased Antigenic Stimulation for Rapid Antibody Maturation (IPAS-RAM) to induce 4E10/10E8-like bnAbs. Rabbits were immunized sequentially, but in a phased manner, with three immunogens that are progressively more native (gp41-28×3, gp41-54CT, and rVV-gp160DH12). Although nAbs were not induced, epitope-mapping analyses indicated that IPAS-RAM vaccination was better able to target antibodies towards the 4E10/10E8 epitopes than homologous prime-boost immunization using gp41-28×3 alone...
February 23, 2017: Virology
https://www.readbyqxmd.com/read/28230658/engineering-antibody-like-inhibitors-to-prevent-and-treat-hiv-1-infection
#19
Matthew R Gardner, Michael Farzan
PURPOSE OF REVIEW: Here we discuss recently developed HIV-1 entry inhibitors that can target multiple epitopes on the HIV-1 envelope glycoprotein (Env), with an emphasis on eCD4-Ig. Some of these inhibitors are more potent and broader than any single antibody characterized to date. We also discuss the use of recombinant adeno-associated virus (rAAV) vectors as a platform for long-term expression of these inhibitors. RECENT FINDINGS: Much of the exterior of HIV-1 Env can be targeted by broadly neutralizing antibodies (bNAbs)...
February 21, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28230657/stabilized-hiv-1-envelope-glycoprotein-trimers-for-vaccine-use
#20
Max Medina-Ramírez, Rogier W Sanders, Quentin J Sattentau
PURPOSE OF REVIEW: To provide an update on the latest developments in the field of HIV-1 antibody-based soluble envelope glycoprotein (Env) trimer design for vaccine use. RECENT FINDINGS: The development of soluble native-like HIV-1 Env trimer immunogens has moved the field of antibody-based vaccine design forward dramatically over the past few years with refinement of various stabilizing approaches. However, despite this progress, significant challenges remain...
February 21, 2017: Current Opinion in HIV and AIDS
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