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In Vitro And In Vivo Affinity Maturation Of Edited B Cells Expressing Hiv 1 Broadly Neutralizing Antibodies
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Book Synopsis In Vitro and in Vivo Affinity Maturation of Edited B Cells Expressing HIV-1 Broadly Neutralizing Antibodies by : Fangzhu Zhao
Download or read book In Vitro and in Vivo Affinity Maturation of Edited B Cells Expressing HIV-1 Broadly Neutralizing Antibodies written by Fangzhu Zhao and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis IDENTIFICATION & IN VITRO AFFI by : Shiqiang Lu
Download or read book IDENTIFICATION & IN VITRO AFFI written by Shiqiang Lu and published by Open Dissertation Press. This book was released on 2017-01-26 with total page 254 pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Identification and in Vitro Affinity Maturation of HIV-1 Envelope Glycoprotein-specific Early Intermediate B Cells Isolated From Immortalized Human Naïve B Cell Library" by Shiqiang, Lu, 卢士強, 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: Broadly neutralizing antibodies (bNAbs) against HIV-1 have been increasingly isolated since 2009. The therapeutic and prophylactic values of bNAbs have been well recognized because these antibodies confer full protection in animal models at relatively low concentrations that are achievable by vaccination. However, the development of effective vaccines to induce such antibodies remains a challenge. The bNAbs are highly mutated and often polyreactive. Moreover, the inferred germline antibodies of known bNAbs do not bind recombinant HIV-1 envelopes (Env). Based on these findings, we hypothesized that naive B cells were activated by non-HIV-1 immunogens, which triggered the initial somatic mutations of germline antibody genes. The limited mutations authorized the B cells (intermediate B cells) the ability to bind HIV-1 envelopes. Upon HIV-1 infection or vaccination with Envs, antibody affinity maturation would be further induced, leading to the development of bNAbs. Although HIV-1 intermediate antibodies have recently been isolated from health donors, information about the statute of HIV-1 intermediate B cells in vivo is rare. The main objective of this study is to isolate HIV-1 intermediate B cells from healthy donors followed by characterization and in vitro maturation of the isolated intermediate B cells. A highly efficient EBV transformation method was used to immortalize purified naive B cells from healthy donors. The enrichment of HIV-1 envelope-specific B cells was observed after panning of library with magnetic beads. An HIV-1intermediate B cell line (LCL-P4) was generated which acquired the germinal center-like B cell phenotype, but did not express AID, an enzyme responsible for the initiation of somatic hypermutation in germinal center B cells. Interestingly, the variable region of LCL-P4 heavy chain shares the same VDJ recombination as PG16, a known HIV-1 bNAbs, according to IMGT analysis. Similar to PG16, LCL-P4 also shows preferential binding with gp140 trimers to gp120 or gp41 monomer. This paper is the first report of an HIV-1 intermediate B cell line generated by panning EBV-immortalized naive B cell libraries. To study the in vitro maturation of identified HIV-1 intermediate B cells, a full-length human antibody display platform was established by constructing two lentiviral expression plasmids with distinct antibiotic-resistant genes for the co-expression of IgH and IgLon mammalian cell surface. All the necessary gene fragments encoding the full-length IgG1, except the variable regions, were cloned to the two plasmids. Using a known bNAb b12 as a model Ab, an in vitro antibody affinity maturation system was further developed based on AID-induced somatic hypermutation. AID-induced mutations could be detected in both B and non-B cells. An HcRed reverse assay was conducted, which enabled the early detection of AID-induced mutations. This full-length human antibody display platform and in vitro antibody affinity maturation method may be used to study the mechanisms of B cell development in vivo, as well as for de novo discovery and engineering of human monoclonal antibodies. Subjects: HIV (Viruses) B cells
Book Synopsis In Vitro and in Vivo Affinity Maturation of Edited B Cells Expressing HIV-1 Broadly by : Yiming Yin
Download or read book In Vitro and in Vivo Affinity Maturation of Edited B Cells Expressing HIV-1 Broadly written by Yiming Yin and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antibodies are essential for humoral immunity, and for effective vaccines. Most antibodies against HIV-1 have limited breadth and potency, and HIV research has begun to focus on broadly neutralizing antibodies (bnAbs), because they can neutralize multiple HIV strains and provide broad and potent protection of macaques from viral challenge. Therefore, vaccines that elicit such bnAbs may similarly protect humans from HIV infection. The development of CRISPR offers a novel and precise method for reprogramming B cells to express newly introduced bnAbs by introducing their variable regions into the B-cell receptor (BCR) loci. Recent studies have attempted to modify BCR loci to express a heavy chain or full antibodies. However, none of these studies have successfully affinity matured an introduced bnAb. Here we developed an editing strategy that introduces heavy and light chain- variable regions at their native loci in B cell lines as well as in primary B cells. This strategy is scarless, and leaves all B-cell regulatory sequences intact, enabling these engineered B cells to undergo class switch recombination (CSR) and extensive somatic mutation (SHM). This design also avoids modifications that impair splicing, limit BCR expression, or mispair heavy and light chains, problems observed with previous B-cell editing strategies. Using this native loci-editing approach, we affinity matured two bnAbs in vitro and in vivo to generate better antibodies with greater potency and breadth. The development of CRISPR offers a novel and precise method for reprogramming B cells to express newly introduced bnAbs by introducing their variable regions into the B-cell receptor (BCR) loci. Recent studies have attempted to modify BCR loci to express a heavy chain or full antibodies. However, none of these studies have successfully affinity matured an introduced bnAb. Here we developed an editing strategy that introduces heavy and light chain- variable regions at their native loci in B cell lines as well as in primary B cells. This strategy is scarless, and leaves all B-cell regulatory sequences intact, enabling these engineered B cells to undergo class switch recombination (CSR) and extensive somatic mutation (SHM). This design also avoids modifications that impair splicing, limit BCR expression, or mispair heavy and light chains, problems observed with previous B-cell editing strategies. Using this native loci-editing approach, we affinity matured two bnAbs in vitro and in vivo to generate better antibodies with greater potency and breadth. First, we assessed the utility of a B cell-based in vitro selection strategy using a V1V2- glycan/apex bnAb, CAP256.VRC26.25 (VRC26.25). VRC26.25 is more potent than most other bnAbs but it has relatively limited breadth. We show that VRC26.25 heavy and light- chain genes were successfully edited by CRISPR/Cas12a into BCRs of a human B cell line. These genes were diversified by introduction of a highly active activation-induced deaminase (AID) variant, and through homology-directed repair (HDR) using soft-randomized DNA templates. High-affinity B cells were then iteratively selected with HIV-1 envelope glycoprotein (SOSIP) trimers. Selected antibody variants were more potent and could neutralize some VRC26.25-resistant isolates, indicating that this approach could be used to improve the breadth as well as potency of antibodies. Second, we developed an in vivo system to affinity mature antibodies in mice. We used VRC26.25 and 10-1074, a V3-glycan bnAb, to demonstrate that engineered B cells can respond appropriately to an immunogen. To achieve this, murine primary B cells were activated and electroporated to express both heavy and light chains of VRC26.25 or 10-1074. These modified murine primary B cells were then engrafted back into recipient mice. We demonstrate that engineered B cells enter germinal centers (GC), secrete antibodies in serum, and form durable memory after antigenic stimulations. B cells carrying VRC26.25 or 10-1074 genes undergo extensive SHM and selection in the GC. The resulting antibody variants were more potent, demonstrating they affinity matured in vivo.
Book Synopsis HIV-Induced Damage of B Cells and Production of HIV Neutralizing Antibodies by : Francesca Chiodi
Download or read book HIV-Induced Damage of B Cells and Production of HIV Neutralizing Antibodies written by Francesca Chiodi and published by Frontiers Media SA. This book was released on 2018-03-27 with total page 171 pages. Available in PDF, EPUB and Kindle. Book excerpt: Multiple dysfunctions take place in the B cell compartment during HIV-1 infection, comprising depletion of resting memory B cells carrying serological memory to vaccines and previously met pathogens. In addition, population of B cells characterized by the expression of exhaustion markers are enlarged during HIV-1 infection. Antibodies with the capacity to neutralize a broad range of HIV-1 isolates can be detected only in a minority of infected patients, after a year or more from acute infection. An open question is whether the inability of producing neutralizing HIV-1 antibodies is somehow linked to the B cell immunopathology observed in patients. In this research topic we invited scientists to summarize the current state of knowledge on regulation and development of B cells and antibody responses during HIV-1 infection; fifteen contributions were received comprising both reviews and original articles. The articles are related to B cell dysfunctions identified in HIV-1 infected individuals, production of different types of antibodies (neutralizing versus non neutralizing, and of different isotypes) in vivo during HIV-1 infection and the biological factors which may impact on this process, clinical potential and applications of anti-HIV antibodies and how to achieve neutralizing antibody responses to HIV-1 epitopes upon vaccination. The topic has gathered articles on front-line research undertaken in the field of B cells and antibodies in HIV-1 infection. It is our hope that the collection of articles presented in this book may be useful for new and experienced scholars in the field and add a piece to the complex puzzle of knowledge needed for the development of an HIV-1 vaccine.
Book Synopsis Vaccine Adjuvants by : Derek T. O’Hagan
Download or read book Vaccine Adjuvants written by Derek T. O’Hagan and published by Springer Science & Business Media. This book was released on 2008-02-02 with total page 343 pages. Available in PDF, EPUB and Kindle. Book excerpt: Derek T. O'Hagan and a team of expert vaccinologists and pharmacologists thoroughly describe the preparation, characterization, and evaluation of a wide range of alternative vaccine adjuvants for use in preclinical studies. Each chapter carefully reviews a single adjuvant, and suggests why a specific adjuvant might be preferred for a given antigen, depending on what type of immune response is desired. Alternate adjuvant choices are also presented so that researchers can choose those most efficacious for their specific purpose. Comprehensive and highly practical, Vaccine Adjuvants: Preparation Methods and Research Protocols provides an effective guide to making and using vaccine adjuvants. By closely following directions from the book, today's researchers will be able optimally to induce specific immune responses against different types of antigens and to selectively manipulate the immune response in a favorable way.
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 HIV-Induced Damage of B Cells and Production of HIV Neutralizing Antibodies by :
Download or read book HIV-Induced Damage of B Cells and Production of HIV Neutralizing Antibodies written by and published by . This book was released on 2018 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Multiple dysfunctions take place in the B cell compartment during HIV-1 infection, comprising depletion of resting memory B cells carrying serological memory to vaccines and previously met pathogens. In addition, population of B cells characterized by the expression of exhaustion markers are enlarged during HIV-1 infection. Antibodies with the capacity to neutralize a broad range of HIV-1 isolates can be detected only in a minority of infected patients, after a year or more from acute infection. An open question is whether the inability of producing neutralizing HIV-1 antibodies is somehow linked to the B cell immunopathology observed in patients. In this research topic we invited scientists to summarize the current state of knowledge on regulation and development of B cells and antibody responses during HIV-1 infection; fifteen contributions were received comprising both reviews and original articles. The articles are related to B cell dysfunctions identified in HIV-1 infected individuals, production of different types of antibodies (neutralizing versus non neutralizing, and of different isotypes) in vivo during HIV-1 infection and the biological factors which may impact on this process, clinical potential and applications of anti-HIV antibodies and how to achieve neutralizing antibody responses to HIV-1 epitopes upon vaccination. The topic has gathered articles on front-line research undertaken in the field of B cells and antibodies in HIV-1 infection. It is our hope that the collection of articles presented in this book may be useful for new and experienced scholars in the field and add a piece to the complex puzzle of knowledge needed for the development of an HIV-1 vaccine.
Book Synopsis Identification and in Vitro Affinity Maturation of HIV-1 Envelope Glycoprotein-specific Early Intermediate B Cells Isolated from Immortalized Human Naïve B Cell Library by : 卢士強
Download or read book Identification and in Vitro Affinity Maturation of HIV-1 Envelope Glycoprotein-specific Early Intermediate B Cells Isolated from Immortalized Human Naïve B Cell Library written by 卢士強 and published by . This book was released on 2015 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Molecular Biology of B Cells by : Tasuku Honjo
Download or read book Molecular Biology of B Cells written by Tasuku Honjo and published by Academic Press. This book was released on 2014-12-22 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular Biology of B Cells, Second Edition is a comprehensive reference to how B cells are generated, selected, activated and engaged in antibody production. All of these developmental and stimulatory processes are described in molecular, immunological, and genetic terms to give a clear understanding of complex phenotypes. Molecular Biology of B Cells, Second Edition offers an integrated view of all aspects of B cells to produce a normal immune response as a constant, and the molecular basis of numerous diseases due to B cell abnormality. The new edition continues its success with updated research on microRNAs in B cell development and immunity, new developments in understanding lymphoma biology, and therapeutic targeting of B cells for clinical application. With updated research and continued comprehensive coverage of all aspects of B cell biology, Molecular Biology of B Cells, Second Edition is the definitive resource, vital for researchers across molecular biology, immunology and genetics.
Book Synopsis HIV-1 Broadly Neutralizing Antibody Precursor B Cells Revealed by Germline-targeting Immunogen by :
Download or read book HIV-1 Broadly Neutralizing Antibody Precursor B Cells Revealed by Germline-targeting Immunogen written by and published by . This book was released on 2016 with total page 6 pages. Available in PDF, EPUB and Kindle. Book excerpt: Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. We employed deep mutational scanning and multi-target optimization to develop a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. Lastly, these methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.
Book Synopsis Eliciting VRC01-class Antibodies Against HIV-1 Through Immunization by : Katherine Rachael Parks
Download or read book Eliciting VRC01-class Antibodies Against HIV-1 Through Immunization written by Katherine Rachael Parks and published by . This book was released on 2020 with total page 222 pages. Available in PDF, EPUB and Kindle. Book excerpt: With more that 37 million people currently infected with HIV-1, there is a need for a vaccine to prevent HIV-1 infection. One goal of an effective HIV-1 vaccine is to elicit broadly neutralizing antibodies (bnAbs). These antibodies (Abs) neutralize the majority of HIV-1 viruses in circulation. bnAbs have been isolated from chronically infected individuals and were shown, in studies of passive administration in non-human primates and humanized mice, to be protective against SHIV and HIV respectively. Thus, it is thought that if bnAbs can be elicited through vaccination, they will be protective.VRC01-class Abs are amongst the most broad and potent neutralizing and therefore desirable to elicit during vaccination. VRC01-class Abs target the CD4-binding site (CD4-BS) on the HIV-1 Env. All members of this class have high levels of somatic hypermutation (SHM); share similar gene ontogenies, all utilizing the VH1-2*02 allele in the heavy chain paired with one of the following light chains: k3-20, k1-33, l2-14, k3-15, k1-5; and use the same mode of recognition to engage the CD4-BS. A major roadblock to eliciting such Abs is the fact that the unmutated or germline precursors which gives rise to these bnAbs fail to bind known recombinant Env. This has led to the development of immunogens that engage the germline (gl)VRC01 precursor, thus named germline-targeting immunogens. This thesis examines germline-targeting immunogens in vivo. The germline-targeting immunogens evaluated are Env-based and also anti-idiotypic antibodies (aiAbs). In Chapter II we evaluated Env-based germline-targeting immunogens. In these studies, we utilized a mouse model expressing B cells with the glVRC01 heavy chain (glH-VRC01 mouse, Table 1.3). Mice were immunized with one of the following germline-targeting immunogens: 426c Core, eOD- GT8, or 426cOD. These immunogens differ in their affinity for glVRC01, the structural presentation of the glVRC01 epitope, and genetically. We found that while all of the glVRC01- targeting immunogens effectively activated VRC01-like B cells in vivo, the immunogens selected for B cells with distinct genetic characteristics that influence their ability to recognize diverse Env proteins. These results will inform HIV-1 vaccine design, as both 426c Core and eOD-GT8 are being evaluated in human clinical trials. These results are also more broadly applicable to vaccine design, by highlighting the importance of structure and biophysical and biochemical properties of the immunogen on B cell activation. While, these germline-targeting immunogens are able to activate VRC01-like B cells in vivo, the Abs they produce are non-neutralizing. Therefore in the work reported in Chapter III, we employed a boosting immunogen in an effort to guide the maturation of these B cells to their neutralizing form. We found that priming glH-VRC01 mice with the germline-targeting immunogen 426c Core and boosting with the HxB2 wild type (WT) Core protein increased SHM in the VRC01-like B cell receptors, improved Ab binding to diverse Env proteins and increasedthe Abs ability to neutralize the autologous WT virus. This work is the first to identify a prime- boost immunization scheme that can elicit VRC01-class Abs capable of neutralizing a WT virus. We also evaluated the aiAb, iv8, as a glVRC01-class germline-targeting immunogen in Chapter IV. In an adoptive transfer experiment, we found that iv8 is able to activate and expand B cells expressing the mature 3BNC60 heavy chain and gl3BNC60 light chain (SI-3BNC60, Table 1.3), as well as decrease the non-VRC01-epitope targeted plasma Ab response in comparison to an Env-based immunogen. Iv8 was also able to expand B cells expressing VRC01-class characteristics in the glH-3BNC60 mouse model. Therefore, we have demonstrated that iv8 can activate glVRC01-class B cells in vivo and should be considered for use in combination or as an alternative to Env-based immunogens in vaccination studies designed to elicit VRC01-class bnAbs.
Book Synopsis EXPLORING THE HUMAN GENOMIC DN by : Yu Zhang
Download or read book EXPLORING THE HUMAN GENOMIC DN written by Yu Zhang and published by Open Dissertation Press. This book was released on 2017-01-26 with total page 236 pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Exploring the Human Genomic DNA Antibody Repertoire for Development of an Effective HIV-1 Vaccine" by Yu, Zhang, 張宇, 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-1 broadly neutralizing antibodies (bnAbs) with great potency and breadth have been identified from approximately 10 to 30% HIV-1 infected individuals with protection against viral infections in vitro and in vivo. However, no vaccine candidates have induced antibodies comparable to known HIV-1 bnAbs in neutralization so far. Besides the envelope plasticity, glycan shield and other tricky viral strategies, lack of detectable binding of bnAbs' predicted germline antibodies to HIV-1 envelope proteins (Env)could account for the failure. After endeavoring to obtain engineered Env proteins capable of triggering the initiation of B cell receptor (BCR) maturation of some known germline bnAbs, it has not been successful to mature them in vitro. It is unknown whether these putative germline antibodies or some unknown germline antibodies could mature to bnAbs. It is also unknown the frequency of these rearranged germline bnAbs in human antibody gene repertoire and the mechanisms of antibody somatic maturation. This study focuses on the exploration of genomic DNA antibody repertoires to help answer these questions, which may ultimately helpHIV-1 vaccine development. The unusual characteristics of the known HIV-1 bnAbs such as extremely high somatic mutation level, long CDR3s and polyreactivity which may halt their maturation process, the preference in lineage usageof currently known bnAbs, as well as the prevalent events of clonal deletion, anergy, and other negative regulations in immune system led us hypothesize that genomic DNA antibody repertoire, before and impervious to any transcriptional or translational regulation, may be more suitable than cDNA antibody repertoire for studying the development of bnAbs. The genomic DNA antibody repertoire may be more diverse than the cDNA antibody repertoire in antibody gene lineage utilization and may have more antibodies or germline antibodies with potential to mature to bnAbs. To investigate human genomic DNA antibody repertoire, large genomic DNA and cDNA antibody libraries from both healthy and HIV-1 infected individuals'peripheral blood mononuclear cells were constructed. 454 deep sequencing result showed that genomic DNA antibody libraries were more diverse than cDNA libraries in lineage usage, yet with extremely low frequencies of the exactly recombined germline genes of bnAbs which may be one of the reasons for the failure in eliciting bnAbs. However, there were relatively higher frequencies of antibodies using other germline gene recombinations with the potential to develop to bnAbs. These findings were further confirmed by the result from panning genomic DNA antibody libraries. A panel of germline and germline-like antibodies, that use diverse V(D)J recombinations have good binding affinity for various HIV-1 envelope proteins were isolated from the genomic DNA antibody libraries but not the corresponding cDNA libraries. They showed improved binding affinity and obtained neutralization ability following the very early steps of in vitro maturation, indicating their potential development to broadly neutralizing antibodies. These results indicate that exploring the genomic DNA antibody repertoire may facilitate the isolation of germline antibodies with potential to mature to bnAbs and the understanding of the mechanisms for the maturation of bnAbs in vivo, which may eventually help HIV-1 vaccine development.
Book Synopsis Biological Diversity by : Anne E. Magurran
Download or read book Biological Diversity written by Anne E. Magurran and published by Oxford University Press. This book was released on 2011 with total page 364 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides an up to date review of the methods of measuring and assessing biological diversity, together with their application.
Book Synopsis HIV-1 Infection and Loss of Serological Memory by :
Download or read book HIV-1 Infection and Loss of Serological Memory written by and published by . This book was released on 2009 with total page 46 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 Isolation and Characterization of HIV-1 Neutralizing Antibodies from Infants by : Cassandra Simonich
Download or read book Isolation and Characterization of HIV-1 Neutralizing Antibodies from Infants written by Cassandra Simonich and published by . This book was released on 2018 with total page 175 pages. Available in PDF, EPUB and Kindle. Book excerpt: Developing a protective HIV vaccine remains a key goal of prevention efforts. Broadly neutralizing antibodies (bnAbs) that recognize diverse circulating strains of HIV are thought to be an important component of a protective vaccine but eliciting such responses remains elusive. bnAbs that have been isolated from HIV-infected adults exhibit several unusual features that present obstacles to their elicitation such as the requirement for high levels of somatic hypermutation (SHM) and long-term antibody maturation for broad activity. Efforts are ongoing to characterize the development of bnAbs following infection to guide immunogen design and vaccine strategies to elicit them despite these immunological barriers. HIV-infected infants develop bnAbs with more rapid kinetics than adults, suggesting that infant responses could inform a more straightforward path to achievable vaccine targets. To understand these unique pediatric responses, we isolated and characterized infant HIV-neutralizing antibodies (nAbs) and defined the development of an infant-derived bnAb. First, we isolated nAbs contributing to a broad plasma response at one year post-infection from infant BF520. We observed that polyclonal nAbs with low SHM contribute to plasma neutralizing activity. Additionally, we isolated one infant-derived bnAb that targets a known conserved site of vulnerability on HIV envelope (Env) commonly targeted by adult bnAbs. This infant bnAb is distinct from adult bnAbs in that it utilizes different germline genes, has very low SHM, and importantly, lacks rare insertions and deletions that have been shown to be critical for the activity of most adult antibodies targeting this epitope. The identification of this infant bnAb illustrates that HIV-1-specific neutralization breadth can develop without prolonged affinity maturation and extensive SHM. Next, we characterized the ontogeny of the infant-derived bnAb by reconstructing the naïve progenitor and developmental intermediates. We observed that the naïve antibody recognizes HIV Env, which contrasts with precursors of many adult bnAbs. The ability to neutralize viruses from multiple clades developed within six months of infection and the full breadth of the mature antibody was reached with as little as 3% SHM. Remarkably, substitutions in the kappa chain enabled both autologous and heterologous neutralization. This study provides a template for the design of vaccine strategies to elicit similar responses by identifying Env isolates that could be used as sequential immunogens. Finally, we isolated and characterized nAbs contributing to plasma breadth at two years post-infection from infant BG505. This infant is of particular interest to the HIV field because the Env of the transmitted virus from BG505 has been extensively characterized in numerous structural and vaccine studies, and understanding the nAbs that developed following infection with this Env complements those studies. We isolated polyclonal nAbs from multiple expanded clonal families contributing to heterologous neutralizing activity. These studies showed that infant antibodies have features distinct from adult antibodies, including several that may be amenable to better vaccine responses. This work represents the first isolation and characterization of a HIV-bnAb from an infant and highlights the potential of the infant immune system to develop polyclonal nAbs against HIV. Future studies should focus on characterizing nAbs contributing to broad plasma responses in additional infants to inform how to elicit bnAbs by vaccination.
Book Synopsis In Vivo Evolution of HIV-1 Neutralizing Antibodies from Engineered B-cell Repertoires by : Tianling Ou
Download or read book In Vivo Evolution of HIV-1 Neutralizing Antibodies from Engineered B-cell Repertoires written by Tianling Ou and published by . This book was released on 2021 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
