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Optimal Combinations Of Broadly Neutralizing Antibodies For Prevention And Treatments Of Hiv 1 Clade C Infection
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Book Synopsis Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatments of HIV-1 Clade C Infection by :
Download or read book Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatments of HIV-1 Clade C Infection written by and published by . This book was released on 2016 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: In this study, the identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.
Book Synopsis Novel Concepts in Using Broadly Neutralizing Antibodies for HIV-1 Treatment and Prevention by : Philipp Schommers
Download or read book Novel Concepts in Using Broadly Neutralizing Antibodies for HIV-1 Treatment and Prevention written by Philipp Schommers and published by Frontiers Media SA. This book was released on 2022-02-09 with total page 182 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Functional Screening for Potent Broadly Neutralizing HIV-1 Human Monoclonal Antibodies and Identification of Dominant Adcc Epitopes on HIV-1 Envelope Glycoprotein by : Zehua Sun
Download or read book Functional Screening for Potent Broadly Neutralizing HIV-1 Human Monoclonal Antibodies and Identification of Dominant Adcc Epitopes on HIV-1 Envelope Glycoprotein written by Zehua Sun and published by Open Dissertation Press. This book was released on 2017-01-26 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Functional Screening for Potent Broadly Neutralizing HIV-1 Human Monoclonal Antibodies and Identification of Dominant ADCC Epitopes on HIV-1 Envelope Glycoprotein" by Zehua, Sun, 孫澤華, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: HIV/AIDS has become a global pandemic. Development of an effective HIV-1 vaccine eliciting broadly neutralizing monoclonal antibodies (bnmAbs) remains a big challenge. Novel approaches for prevention and treatment of HIV-1 infection may alleviate the burden caused by the pandemic. About 20% HIV-1-infected individuals can develop strong B cell response within 3-5 months after infection, and 3-5% HIV-1-infected individuals can generate high titers of bnAbs within 1-2 years during chronic infection. Many bnAbs have been isolated against different epitopes, including 2G12, 2F5, 4E10, m43, b12, x5, VRC01 like antibodies, PG9, PG16, PGT121-128 and 10E8. Most of these antibodies were isolated based on binding affinities. However, binding affinity does not necessarily correlate with neutralizing abilities. For the purpose of facilitating the bnmAbs screening, a novel methodology for isolating HIV-1 bnmAbs directly based on antibody neutralization activity has been developed. Immune recombinant full length IgGs libraries were displayed on target cell surface followed by sorting the cells by antibody neutralization ability. After several rounds of sorting, a panel of human cell-associated mAbs has been isolated that can neutralize various isolates from different Chinese clades when displayed on the surface of mammalian cells. Several isolated antibodies have been converted into soluble version for purification and characterization. Three mAbs (FS1416, FS1476 and FS1482) were identified to be able to neutralize several Chinese circulating viruses. These antibodies showed the complementary neutralizing profiles to existing antibody b12 which allows for a broadly neutralizing of 50% virus isolates from Africa and American. Our results indicate the discovery of novel antibodies which may have the application to use jointly with other existing antibodies to largely extend the current neutralizing spectrum. Antibody-dependent cell-mediated cytotoxicity (ADCC) has been observed associated with the reduced risk of HIV acquisition in RV144 vaccine trial. And an increasing number of evidences shows that ADCC activity correlates with enhanced HIV-1 control, retards the progression of disease, strongly suggesting the importance of antibody effector functions in immune protection against HIV-1. HIV-1 envelope glycoprotein gp160 has been shown to be highly immunogenic and thus is considered as the most important target for immune protection. Although a few neutralizing epitopes which are targeted by human potent broadly neutralizing antibodies have been studied there was no study about ADCC epitopes on HIV-1. Here, this issue has been addressed by yeast display based epitope mapping of serum purified IgG from HIV-1 infected long term non progressors with different ADCC activities in China. As a result, four dominant ADCC epitopes were identified on HIV-1 HXB2 gp160. They were designated D1 (aa 72 to 133), D2 (aa 196-226), and D3 (254-275), which are located in gp120, and D4 (742-824) that is located in gp41. This study would provide a useful information in vaccine design to elicit both potent neutralizing and strong ADCC activity antibodies, which could be used for protection against HIV-1 infection. In summary, this novel methodology generated for functional screening of broadly neutralizing antibodies and potential
Book Synopsis Complete Mapping of HIV-1 Escape from Broadly Neutralizing Antibodies, Vaccines, and Drugs by : Adam S. Dingens
Download or read book Complete Mapping of HIV-1 Escape from Broadly Neutralizing Antibodies, Vaccines, and Drugs written by Adam S. Dingens and published by . This book was released on 2019 with total page 132 pages. Available in PDF, EPUB and Kindle. Book excerpt: The expansive global diversity of HIV-1 Env presents significant hurdles in developing a broadly protective vaccine. This diversity is a result of HIV Env’s exceptional evolutionary capacity, which allows it to evade the extraordinary diversity of the humoral immune system during infection. However, the evolutionary arms race between Env and humoral immunity occasionally drives the development of broadly neutralizing antibodies (bnAbs) capable of neutralizing diverse strains. Mapping the epitope specificity of bnAbs has revealed conserved regions of Env, which are promising targets for structure-based vaccine design. Additionally, bnAbs’ broad activity and potential to direct the killing of infected cells make them promising antiviral immunotherapeutic drugs for HIV prevention, therapy, and cure strategies. Translating bnAbs into vaccines and therapies will require both a detailed understanding of how bnAbs interact with Env as well as assessing their potential for viral escape. While structural studies provide atomic-level views of HIV-antibody interactions, they fail to reveal the functional interactions necessary for neutralization and the viral mutations that disrupt these interactions. Neutralization and binding assays using mutants can provide such information for specific mutations, but even the largest studies employing one-at-a-time mutagenesis can only assay a small fraction of all possible Env mutations. To overcome these shortcomings, we have developed mutational antigenic profiling, a deep mutational scanning approach that completely maps the functional interface between HIV and an antibody in a single massively parallel experiment. This involves generating libraries of HIV that carry all possible amino-acid mutations to Env (12,730 amino-acid mutations), incubating these viral libraries with or without an antibody, infecting T cells, and using deep sequencing to quantify the enrichment of each mutation in the antibody selected versus non-selected libraries. Profiling escape from bnAb PGT151 identified all previously known and revealed numerous additional escape mutations. Benchmarking these data against traditional neutralization assays further validated that we accurately quantified the effect of all amino-acid mutations to Env. Additionally, evaluating the effect of each amino acid at each site elucidated the biochemical mechanisms of escape throughout the epitope, highlighting the previously unappreciated role for charge-charge repulsions. To gain a broad view of HIV antibody escape, we mapped escape from a panel of nine bnAbs targeting the five best-characterized Env epitopes. Importantly, many of these bnAbs are being clinically developed as immunotherapeutics. While prior studies had defined each of these bnAbs’ structural epitope, our unbiased mapping defined their functional epitopes, or the sites at which mutations mediated escape in the context of replication competent viruses, for the first time. For most bnAbs, mutations at only a small fraction of structurally defined contact sites mediated escape, and escape often occurred at sites that are near but do not directly contact the antibody. Further, these data helped to interpret viral mutations observed in immunotherapy clinical trials—in vivo escape occurred in the functional epitope, some of which was previously missed since it was far from the structural epitope. Additionally, this data allowed for an unbiased quantification of the ease of viral escape for each bnAb, which we found is distinct from antibody breadth. We also mapped escape from a pool of two bnAbs; we found that there were no mutations that robustly escaped both antibodies, agreeing with the results of two recently completed clinical trials that administered this combination. Further, we profiled escape from two antibodies across multiple viral strains, providing the first unbiased quantifications of strain-specific differences in antibody escape. Next, we leveraged mutational antigenic profiling to directly refine structure-based vaccine design. We contrasted escape from bnAb VRC34.01 with escape from two murine antibodies that were elicited with immunogens based on the VRC34.01 epitope. This revealed distinct differences in the recognition of natural and vaccine-elicited antibodies, and provide a template to guide the iterative rounds of vaccine design. We then adapted this approach to better delineate the genotypic determinants of resistance to the only clinically approved HIV fusion inhibitor, enfuvirtide. Again, we identified both previously characterized and novel resistance mutations. Many resistance mutations were allosteric to the drug’s binding site, which shed light on diverse mechanisms of resistance. Further, this complete map of resistance may be of use in the clinical monitoring of resistance during therapy and the genotypic prediction of enfuvirtide sensitivity prior to treatment. Few protein-protein interfaces have been as heavily studied as those between bnAbs and Env, as these interactions provide the motivation for many HIV treatment and prevention efforts. Mutational antigenic profiling yields an unprecedented view of these interfaces, redefining out understanding of an antibody’s functional epitope. The complete maps of viral escape detailed in this thesis provide a mutation-level antigenic atlas for understanding viral immune escape and guiding the development of antibody immunotherapies and vaccines.
Book Synopsis The HIV-1 Envelope Glycoproteins by : Rogier Willem Sanders
Download or read book The HIV-1 Envelope Glycoproteins written by Rogier Willem Sanders and published by Amsterdam University Press. This book was released on 2003-12-01 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: The need for a vaccine against HIV is obvious, but the development of an effective vaccine has met with frustrations. The HIV envelope glycoproteins, residing in the viral membrane, are the sole viral proteins exposed on the outside of virus particles and.
Book Synopsis AIDS Research and Reference Reagent Program Catalog by :
Download or read book AIDS Research and Reference Reagent Program Catalog written by and published by . This book was released on 2001 with total page 356 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Journal by : North Dakota Legislative Assembly House
Download or read book Journal written by North Dakota Legislative Assembly House and published by . This book was released on 2015-09-30 with total page 898 pages. Available in PDF, EPUB and Kindle. Book excerpt: This work has been selected by scholars as being culturally important, and is part of the knowledge base of civilization as we know it. This work was reproduced from the original artifact, and remains as true to the original work as possible. Therefore, you will see the original copyright references, library stamps (as most of these works have been housed in our most important libraries around the world), and other notations in the work.This work is in the public domain in the United States of America, and possibly other nations. Within the United States, you may freely copy and distribute this work, as no entity (individual or corporate) has a copyright on the body of the work.As a reproduction of a historical artifact, this work may contain missing or blurred pages, poor pictures, errant marks, etc. Scholars believe, and we concur, that this work is important enough to be preserved, reproduced, and made generally available to the public. We appreciate your support of the preservation process, and thank you for being an important part of keeping this knowledge alive and relevant.
Book Synopsis The CAPRISA Clinical Trials: HIV Treatment and Prevention by : Quarraisha Abdool Karim
Download or read book The CAPRISA Clinical Trials: HIV Treatment and Prevention written by Quarraisha Abdool Karim and published by Springer. This book was released on 2017-01-20 with total page 237 pages. Available in PDF, EPUB and Kindle. Book excerpt: Since its inception 14 years ago, CAPRISA has conducted numerous clinical studies that have influenced international TB-HIV treatment guidelines as well as HIV prevention through innovations in the microbicide and vaccine fields. This book provides a historical account of how each of CAPRISA’s high impact studies was created, developed, implemented, analysed and communicated. In doing so, the reader is taken on a journey that provides glimpses into the genesis of research ideas and how this ultimately leads to a range of HIV prevention and treatment studies that have impacted the global response to the HIV and TB epidemics. Comprised of 5 sections, the book details the following: HIV epidemic in South Africa and the establishment of a research centre to undertake clinical, epidemiological and laboratory research on HIV. CAPRISA’s clinical trials on HIV and HSV-2 prevention. These studies investigated the impact of tenofovir gel as topical antiretroviral pre-exposure prophylaxis (PrEP), implementation of topical PrEP through family planning clinics, conditional cash incentives for HIV prevention, HIV vaccines, and passive immunisation with broadly neutralising antibodies. CAPRISA’s research on the treatment of HIV and TB co-infection. A review of the major scientific findings from the CAPRISA studies on acute infection and genital mucosal immunology. Essential support activities for the conduct of clinical trials, including research laboratories and pharmacies, as well as establishing effective communication and sustainable structures for community engagement to maintain effective and respectful partnerships with participating communities. The book concludes with a chapter about the challenges facing future HIV prevention and treatment trials. The CAPRISA Clinical Trials: HIV Treatment and Prevention is a resource for undergraduate and postgraduate students, health care providers, doctors, decision-makers and researchers who are seeking guidance and insights on clinical trials – their creation, conduct and impact.
Book Synopsis Optimization of an HIV-1 Clade C DNA Vaccine by : Luca Melnychuk
Download or read book Optimization of an HIV-1 Clade C DNA Vaccine written by Luca Melnychuk and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Recent studies have identified sites on the HIV-1 Env that are vulnerable to neutralizing antibodies. One of these sites is located at the C-terminus of the gp41 ectodomain (gp41ecto), the membrane proximal external region (MPER). The MPER is a highly conserved sequence that binds multiple broadly neutralizing antibodies (bNAb). Efforts to produce a gp41 immunogen have been in part hampered by its hydrophobicity and propensity to aggregate. Our work focuses on developing a DNA vaccine to target the MPER. Our objective was to generate a gp41ecto DNA vaccine that could be secreted from mammalian cells and maintain binding by bNAbs. Through in silico analysis, we predicted regions of gp41ecto that could cause aggregation and hinder secretion. We generated several deletion mutants of gp41ecto and transfected them in mammalian cells. We were able to identify regions that hindered the secretion of gp41ecto using immunoblot and ELISA based methods performed on cell supernatants. Upon deletion of regions in the fusion peptide (FP) and MPER, secretion of the gp41ecto increased. However, the deletion in the MPER contained the epitopes for multiple bNAbs. In order to maintain binding by bNAbs and increased secretion, we developed constructs with the FP deletion and introduced point mutations in the MPER. We used an ELISA based method to determine binding of bNAbs to our gp41ecto constructs. Only one of our constructs was able to bind the bNAbs 4E10, Z13e1 and 10E8: gp41 [DELTA]FP+I682E. This construct was injected into a small animal model to determine immunogenicity. Using an ELISA based method, the gp41 [DELTA]FP+I682E construct showed no increase in total IgG response compared to the gp41 [DELTA]FP construct, although a modest increase response towards the MPER compared to gp41 [DELTA]FP was noted." --
Book Synopsis WHO preferred product characteristics for monoclonal antibodies for HIV prevention by : World Health Organization
Download or read book WHO preferred product characteristics for monoclonal antibodies for HIV prevention written by World Health Organization and published by World Health Organization. This book was released on 2022-05-31 with total page 43 pages. Available in PDF, EPUB and Kindle. Book excerpt: This document describes World Health Organization (WHO) preferences for characteristics of monoclonal antibody (mAb) products used for passive immunization against HIV. These preferences are shaped by the global unmet public health need in priority disease areas for which WHO encourages the development of vaccines and other preventive interventions suitable for use in low- and middle-income countries (LMICs).
Book Synopsis Chimpanzees in Biomedical and Behavioral Research by : National Research Council
Download or read book Chimpanzees in Biomedical and Behavioral Research written by National Research Council and published by National Academies Press. This book was released on 2011-12-05 with total page 200 pages. Available in PDF, EPUB and Kindle. Book excerpt: For many years, experiments using chimpanzees have been instrumental in advancing scientific knowledge and have led to new medicines to prevent life-threatening and debilitating diseases. However, recent advances in alternate research tools have rendered chimpanzees largely unnecessary as research subjects. The Institute of Medicine, in collaboration with the National Research Council, conducted an in-depth analysis of the scientific necessity for chimpanzees in NIH-funded biomedical and behavioral research. The committee concludes that while the chimpanzee has been a valuable animal model in the past, most current biomedical research use of chimpanzees is not necessary, though noted that it is impossible to predict whether research on emerging or new diseases may necessitate chimpanzees in the future.
Book Synopsis Fc-Mediated Antibody Functions and Fc-Receptor Polymorphism by : Guido Ferrari
Download or read book Fc-Mediated Antibody Functions and Fc-Receptor Polymorphism written by Guido Ferrari and published by Frontiers Media SA. This book was released on 2020-07-28 with total page 273 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Exploring Novel Approaches to Eliminate HIV Reservoirs to Achieve a Cure for HIV by : Renee Marije Van Der Sluis
Download or read book Exploring Novel Approaches to Eliminate HIV Reservoirs to Achieve a Cure for HIV written by Renee Marije Van Der Sluis and published by Frontiers Media SA. This book was released on 2021-04-07 with total page 111 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book HIV-1 Latency written by Guido Silvestri and published by Springer. This book was released on 2018-10-11 with total page 253 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume summarizes recent advances in understanding the mechanisms of HIV-1 latency, in characterizing residual viral reservoirs, and in developing targeted interventions to reduce HIV-1 persistence during antiretroviral therapy. Specific chapters address the molecular mechanisms that govern and regulate HIV-1 transcription and latency; assays and technical approaches to quantify viral reservoirs in humans and animal models; the complex interchange between viral reservoirs and the host immune system; computational strategies to model viral reservoir dynamics; and the development of therapeutic approaches that target viral reservoir cells. With contributions from an interdisciplinary group of investigators that cover a broad spectrum of subjects, from molecular virology to proof-of-principle clinical trials, this book is a valuable resource for basic scientists, translational investigators, infectious-disease physicians, individuals living with HIV/AIDS and the general public.
Book Synopsis Encyclopedia of AIDS by : Thomas J. Hope
Download or read book Encyclopedia of AIDS written by Thomas J. Hope and published by . This book was released on with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Clinical Virology by : Douglas D. Richman
Download or read book Clinical Virology written by Douglas D. Richman and published by John Wiley & Sons. This book was released on 2020-07-10 with total page 1489 pages. Available in PDF, EPUB and Kindle. Book excerpt: The essential reference of clinical virology Virology is one of the most dynamic and rapidly changing fields of clinical medicine. For example, sequencing techniques from human specimens have identified numerous new members of several virus families, including new polyomaviruses, orthomyxoviruses, and bunyaviruses. Clinical Virology, Fourth Edition, has been extensively revised and updated to incorporate the latest developments and relevant research. Chapters written by internationally recognized experts cover novel viruses, pathogenesis, epidemiology, diagnosis, treatment, and prevention, organized into two major sections: Section 1 provides information regarding broad topics in virology, including immune responses, vaccinology, laboratory diagnosis, principles of antiviral therapy, and detailed considerations of important organ system manifestations and syndromes caused by viral infections. Section 2 provides overviews of specific etiologic agents and discusses their biology, epidemiology, pathogenesis of disease causation, clinical manifestations, laboratory diagnosis, and management. Clinical Virology provides the critical information scientists and health care professionals require about all aspects of this rapidly evolving field.
Download or read book Antibody Fc written by Margaret Ackerman and published by Academic Press. This book was released on 2013-08-06 with total page 376 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antibody Fc is the first single text to synthesize the literature on the mechanisms underlying the dramatic variability of antibodies to influence the immune response. The book demonstrates the importance of the Fc domain, including protective mechanisms, effector cell types, genetic data, and variability in Fc domain function. This volume is a critical single-source reference for researchers in vaccine discovery, immunologists, microbiologists, oncologists and protein engineers as well as graduate students in immunology and vaccinology. Antibodies represent the correlate of protection for numerous vaccines and are the most rapidly growing class of drugs, with applications ranging from cancer and infectious disease to autoimmunity. Researchers have long understood the variable domain of antibodies, which are responsible for antigen recognition, and can provide protection by blocking the function of their target antigen. However, recent developments in our understanding of the protection mediated by antibodies have highlighted the critical nature of the antibody constant, or Fc domain, in the biological activity of antibodies. The Fc domain allows antibodies to link the adaptive and innate immune systems, providing specificity to a wide range of innate effector cells. In addition, they provide a feedback loop to regulate the character of the immune response via interactions with B cells and antigen-presenting cells. - Clarifies the different mechanisms of IgG activity at the level of the different model systems used, including human genetic, mouse, and in vitro - Covers the role of antibodies in cancer, infectious disease, and autoimmunity and in the setting of monoclonal antibody therapy as well as naturally raised antibodies - Color illustrations enhance explanations of the immune system
