Bibliografías temáticas / Broadly neutralizing antibodies (bNAbs)

Literatura académica sobre el tema "Broadly neutralizing antibodies (bNAbs)"

Autor: Grafiati

Publicado: 27 de julio de 2024

Última modificación: 28 de julio de 2024

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Artículos de revistas sobre el tema "Broadly neutralizing antibodies (bNAbs)"

Karuna, Shelly T. y Lawrence Corey. "Broadly Neutralizing Antibodies for HIV Prevention". Annual Review of Medicine 71, n.º 1 (27 de enero de 2020): 329–46. http://dx.doi.org/10.1146/annurev-med-110118-045506.

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In the last decade, over a dozen potent broadly neutralizing antibodies (bnAbs) to several HIV envelope protein epitopes have been identified, and their in vitro neutralization profiles have been defined. Many have demonstrated prevention efficacy in preclinical trials and favorable safety and pharmacokinetic profiles in early human clinical trials. The first human prevention efficacy trials using 10 sequential, every-two-month administrations of a single anti-HIV bnAb are anticipated to conclude in 2020. Combinations of complementary bnAbs and multi-specific bnAbs exhibit improved breadth and potency over most individual antibodies and are entering advanced clinical development. Genetic engineering of the Fc regions has markedly improved bnAb half-life, increased mucosal tissue concentrations of antibodies (especially in the genital tract), and enhanced immunomodulatory and Fc effector functionality, all of which improve antibodies' preventative and therapeutic potential. Human-derived monoclonal antibodies are likely to enter the realm of primary care prevention and therapy for viral infections in the near future.

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Yang, Guang, Mengfei Liu, Kevin Wiehe, Nathan Nicely, Barton Haynes, John Mascola, Pamela Bjorkman y Garnett Kelsoe. "HIV broadly neutralizing antibodies and immunological tolerance (VAC7P.988)". Journal of Immunology 192, n.º 1_Supplement (1 de mayo de 2014): 141.33. http://dx.doi.org/10.4049/jimmunol.192.supp.141.33.

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Abstract It is generally thought that many human antibodies (Ab) that neutralize multiple clades of HIV-1 (bnAbs) are self-reactive. We previously identified kynureninase as the primary self-antigen recognized by 2F5, suggesting that generation of Ab to the 2F5 epitope of HIV-1 may be proscribed by immune tolerance, a notion supported by impaired B-cell development in mice expressing the 2F5 VH and VL regions. However, there is a lack of quantitative and systemic assessment of polyreactivity among HIV bnAbs. In addition, it is unknown whether other classes of HIV-1 bnAbs and non-neutralizing antibodies are also influenced by immunological tolerance. Here, we used protein microarrays to assess bnAb binding to over 9,600 human proteins and compared bnAb binding profiles to HIV non-neutralizing antibodies. We found that bnAbs as a class are more autoreactive and more polyreactive than non-neutralizers. Interestingly, 4 of 7 CD4bs bnAbs screened from 2 distinct lineages (VRC01, VRC02, CH103 and CH106) bind human protein ubiquitin ligase E3A (UBE3A). We confirmed this crossreactivity in ELISA, and demonstrated that UBE3A competitively inhibits gp120 binding to VRC01. Our results demonstrate that HIV-1 bnAbs are significantly more polyreactive and self-reactive than non-neutralizers, which may subject them to immunological tolerance control in vivo. Our identification of UBE3A as a self-antigen of bnAbs provides a mechanism for the rarity and delayed development of certain CD4bs bnAbs.

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Lubow, Jay, Lisa M. Levoir, Duncan K. Ralph, Laura Belmont, Maya Contreras, Catiana H. Cartwright-Acar, Caroline Kikawa et al. "Single B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses". PLOS Pathogens 19, n.º 10 (9 de octubre de 2023): e1011722. http://dx.doi.org/10.1371/journal.ppat.1011722.

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Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasures that avoid enhancement of infection associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following repeated DENV infections. We identified several new bnAbs with comparable or superior breadth and potency to known bnAbs, and with distinct recognition determinants. Unlike all known flavivirus bnAbs, which are IgG1, one newly identified cross-flavivirus bnAb (F25.S02) was derived from IgA1. Both IgG1 and IgA1 versions of F25.S02 and known bnAbs displayed neutralizing activity, but only IgG1 enhanced infection in monocytes expressing IgG and IgA Fc receptors. Moreover, IgG-mediated enhancement of infection was inhibited by IgA1 versions of bnAbs. We demonstrate a role for IgA in flavivirus infection and immunity with implications for vaccine and therapeutic strategies.

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Sprenger, Kayla G., Joy E. Louveau, Pranav M. Murugan y Arup K. Chakraborty. "Optimizing immunization protocols to elicit broadly neutralizing antibodies". Proceedings of the National Academy of Sciences 117, n.º 33 (3 de agosto de 2020): 20077–87. http://dx.doi.org/10.1073/pnas.1919329117.

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Natural infections and vaccination with a pathogen typically stimulate the production of potent antibodies specific for the pathogen through a Darwinian evolutionary process known as affinity maturation. Such antibodies provide protection against reinfection by the same strain of a pathogen. A highly mutable virus, like HIV or influenza, evades recognition by these strain-specific antibodies via the emergence of new mutant strains. A vaccine that elicits antibodies that can bind to many diverse strains of the virus—known as broadly neutralizing antibodies (bnAbs)—could protect against highly mutable pathogens. Despite much work, the mechanisms by which bnAbs emerge remain uncertain. Using a computational model of affinity maturation, we studied a wide variety of vaccination strategies. Our results suggest that an effective strategy to maximize bnAb evolution is through a sequential immunization protocol, wherein each new immunization optimally increases the pressure on the immune system to target conserved antigenic sites, thus conferring breadth. We describe the mechanisms underlying why sequentially driving the immune system increasingly further from steady state, in an optimal fashion, is effective. The optimal protocol allows many evolving B cells to become bnAbs via diverse evolutionary paths.

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Glazkova, D. V., E. V. Bogoslovskaya, G. A. Shipulin y S. M. Yudin. "Broadly neutralizing antibodies for the treatment of HIV infection". HIV Infection and Immunosuppressive Disorders 13, n.º 3 (24 de octubre de 2021): 81–95. http://dx.doi.org/10.22328/2077-9828-2021-13-3-81-95.

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Antibodies with neutralizing activity against a wide range of human immunodeficiency virus 1 subtypes (known as broadly neutralizing antibodies — bNAb) are of great interest as a therapeutic agent for the treatment of HIV infection, because they are able to provide natural protection against most HIV-1 strains. The review discusses the mechanisms of formation of bNAbs, their classification by binding to conservative regions of the envelope protein, as well as their intrinsic features. Description of the most promising bNAbs and their combinations is presented.In the last section the results of clinical trials of 3BNC117, VRC01 and 10-1074 bNAbs available to date are reviewed in detail. An important finding of these studies was that the introduction of a single antibody is followed by the appearance of resistant viral variants. The investigation of the only combination of 3BNC117 and 10-1074 completed so far indicates that combined therapy is more effective and allows to achieve long-term viral suppression in some patients. The promise of combined HIV immunotherapy is evidenced by the initiation of a large number of clinical trials evaluating the efficacy of two or more different bNAbs.

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Shrader, Hannah, Sabrina Helmold Hait, Sarah Lovelace, Meaghan Kilner, Chen-Hsiang Shen, Emily Coates, Martin Gaudinski et al. "Phenotypic analysis of HIV-1 resistance to CD4 binding site broadly-neutralizing antibodies". Journal of Immunology 210, n.º 1_Supplement (1 de mayo de 2023): 223.08. http://dx.doi.org/10.4049/jimmunol.210.supp.223.08.

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Abstract Broadly neutralizing antibodies (bNAbs) show strong immunotherapy potential by targeting conserved regions of the HIV-1 envelope. Single bNAb use in viremic individuals quickly results in the emergence of escape variants, likely originating from existing quasispecies. An ex vivo assay was developed to predict bNAb efficacy in viremic individuals. The development of a predictive bNAb efficacy model may assist with the planning of future clinical trials. The ex vivoassay used pre-infusion CD4 +T cells from participants enrolled in the VRC 607/ACTG A5378 phase I study of the CD4 binding site (CD4bs) bNAbs’ VRC01LS (n=7) or VRC07-523LS (n=9). From these assays, the escape variant signatures of outgrowth viruses that replicated in presence of CD4bs bNAbs, were identified. We found that these escape variants contained key changes to the ß23-V5 region of the gp120 envelope, including charge changes, glycan loss, and/or glycan shifts. Outgrowth viruses from each participant had similar escape mutation patterns. Resistance mutations of the viral env sequences were confirmed in pseudovirus-based neutralization assays. We found complementary escape profiles from 3 CD4bs bNAbs (1–18LS, N6LS, and VRC01v23) with ex vivoand neutralization assays showing suppression by 1 or 2 but not all 3 bNAbs, supporting the potential for combination bNAb therapy. Our data suggest that the simultaneous use of multiple CD4 binding site bNAbs together could aid in limiting viral escape. Supported by intramural funds from NIH.

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Steichen, Jon M., Ying-Cing Lin, Colin Havenar-Daughton, Simone Pecetta, Gabriel Ozorowski, Jordan R. Willis, Laura Toy et al. "A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses". Science 366, n.º 6470 (31 de octubre de 2019): eaax4380. http://dx.doi.org/10.1126/science.aax4380.

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Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer–based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.

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Thavarajah, Jannifer Jasmin, Bo Langhoff Hønge y Christian Morberg Wejse. "The Use of Broadly Neutralizing Antibodies (bNAbs) in HIV-1 Treatment and Prevention". Viruses 16, n.º 6 (4 de junio de 2024): 911. http://dx.doi.org/10.3390/v16060911.

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Background: Although antiretroviral therapy (ART) effectively halts disease progression in HIV infection, the complete eradication of the virus remains elusive. Additionally, challenges such as long-term ART toxicity, drug resistance, and the demanding regimen of daily and lifelong adherence required by ART highlight the imperative need for alternative therapeutic and preventative approaches. In recent years, broadly neutralizing antibodies (bNAbs) have emerged as promising candidates, offering potential for therapeutic, preventative, and possibly curative interventions against HIV infection. Objective: This review aims to provide a comprehensive overview of the current state of knowledge regarding the passive immunization of bNAbs in HIV-1-infected individuals. Main findings: Recent findings from clinical trials have highlighted the potential of bNAbs in the treatment, prevention, and quest for an HIV-1 cure. While monotherapy with a single bNAb is insufficient in maintaining viral suppression and preventing viral escape, ultimately leading to viral rebound, combination therapy with potent, non-overlapping epitope-targeting bNAbs have demonstrated prolonged viral suppression and delayed time to rebound by effectively restricting the emergence of escape mutations, albeit largely in individuals with bNAb-sensitive strains. Additionally, passive immunization with bNAb has provided a “proof of concept” for antibody-mediated prevention against HIV-1 acquisition, although complete prevention has not been obtained. Therefore, further research on the use of bNAbs in HIV-1 treatment and prevention remains imperative.

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Kumar, Rajesh, Huma Qureshi, Suprit Deshpande y Jayanta Bhattacharya. "Broadly neutralizing antibodies in HIV-1 treatment and prevention". Therapeutic Advances in Vaccines and Immunotherapy 6, n.º 4 (agosto de 2018): 61–68. http://dx.doi.org/10.1177/2515135518800689.

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Antibodies that naturally develop in some individuals infected with human immunodeficiency virus 1 (HIV-1) and are capable of broadly neutralizing diverse strains of HIV-1 are useful for two applications: they can inform the rational design of vaccine immunogens, and they may be capable of preventing and treating HIV-1 infection when administered passively. A phase IIb study has been initiated with the experimental broadly neutralizing antibody (bnAb) VRC01, which has considerable breadth and potency (also referred to as a phase IIb HVTN 703/HPTN 081 and HVTN 704/HPTN 085 AMP efficacy trials) to evaluate its protective efficacy in individuals at risk of HIV acquisition. bnAbs prevent HIV-1 infection by selectively targeting vulnerable sites on the viral envelope (Env) protein that facilitates the entry of HIV. Although in very early stages, bnAbs capable of neutralizing a broad range of inter- and intraclade HIV-1 isolates have been demonstrated to have potential in treating patients either alone or in combination with antiretroviral drug therapy (cART); however, they are proposed to be advantageous over the latter as far as durability and side effects are concerned. Recent studies have indicated that combination therapy of potent bnAbs along with latency-reversing agents (LRAs) might also target latent reservoirs of HIV and kill them by recruiting effector cells, such as natural killer cells, thus confirming clinical progression. Possession of such qualities makes these new-generation potent bnAbs extremely valuable in effectively complementing the shortcomings of current ART drugs and improving the quality of life of infected individuals.

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Xu, Ling, Amarendra Pegu, Ercole Rao, Nicole Doria-Rose, Jochen Beninga, Krisha McKee, Dana M. Lord et al. "Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques". Science 358, n.º 6359 (20 de septiembre de 2017): 85–90. http://dx.doi.org/10.1126/science.aan8630.

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The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.

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Tesis sobre el tema "Broadly neutralizing antibodies (bNAbs)"

Nemoz, Benjamin. "Exploration longitudinale à haut débit et en cellule unique du répertoire d'anticorps neutralisants à large spectre chez un neutraliseur d'élite du VIH-1". Electronic Thesis or Diss., Université Grenoble Alpes, 2024. http://www.theses.fr/2024GRALV012.

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L'infection par le virus de l'immunodéficience humaine de type 1 (VIH-1) reste un problème majeur de santé publique à l'échelle mondiale, avec environ 37,7 millions de personnes vivant avec le virus et de nouvelles contaminations dépassant le million de cas par an. Des antirétroviraux efficaces permettent maintenant de traiter durablement les personnes infectées. Ces thérapies contribuent également à améliorer la prévention et à ralentir la progression de l'épidémie. Cependant, un vaccin reste nécessaire, en particulier pour contrôler l'épidémie dans les régions à faible revenu et les environnements précaires.Le rôle protecteur des anticorps neutralisants (AcN) a été démontré sans équivoque dans les modèles animaux d'infection par le VIH et chez l'homme. Par conséquent, le développement d'un vaccin visant à la production, par les cellules B, d'anticorps (Ac) capables de neutraliser la majorité des virus en circulation, à savoir des AcN à large spectre (AcNLS), pourrait être envisagé comme une réponse à la pandémie de VIH.L'étude du développement des AcNLS chez certains individus, dénommés neutraliseurs d’élite du VIH-1, fournit des informations précieuses pour la conception de tels vaccins. Jusqu'à présent, la plupart des études entreprises se sont appuyées sur le tri conventionnel de cellules B uniques par cytométrie en flux (FACS) pour isoler les AcNLS. Dans la présente étude, nous avons utilisé l'approche "Chromium Single Cell Immune Profiling" à haut débit sur cellules uniques (scRNA-seq) pour réaliser une exploration longitudinale du répertoire des cellules B chez un neutraliseur d'élite du VIH-1. Cette méthode permet d'utiliser comme appâts pour l'identification des cellules B spécifiques un nombre beaucoup plus important de glycoprotéines d’enveloppe (Env) du VIH par rapport aux approches d'isolement d'Ac basées sur le FACS, ce qui permet d'obtenir une analyse plus complète du répertoire en Ac anti-Env. En outre, cette approche fournit une multitude d'informations sur la nature des Ac spécifiques identifiés et sur les cellules B correspondantes.Notre étude a permis d'identifier la séquence de 12 130 anticorps spécifiques de la protéine Env du VIH. Des Ac de 39 lignées ont été produits et testés pour leurs capacités de neutralisation, révélant 21 lignées neutralisantes. Ces résultats démontrent la capacité de la méthode à explorer de vastes répertoires spécifiques d'antigènes à partir d'échantillons longitudinaux. L'activité neutralisante des Ac de quatre lignées récapitulait l'activité sérique du donneur, permettant de neutraliser 62,4 % d'un large panel prédictif de 126 pseudovirus. Une de ces lignées neutralisantes ciblait la région riche en mannose de la gp120. Par ailleurs, les Ac de cette lignée étaient sensibles à la présence d'un glycane en position N332. Un seul de ces Ac était responsable de la plus grande partie de cette neutralisation (51,1 %) avec une activité à faible concentration (IC50 moyenne de 91,1 ng.mL-1). Cet Ac possède un CDRH3 de 23 AA de long et 20 % d'hypermutation somatique (SMH). La lignée a montré une maturation continue sur 6,5 ans, avec des taux de SMH observés de 2,0 % à 30,6 % pour la chaîne lourde, sans insertion ou délétion.Un tri conventionnel basé sur la méthode FACS avait été utilisé précédemment pour isoler des AcNLS du même donneur. En comparaison, l'approche scRNA-seq a permis d'isoler des Ac en nombre bien supérieur. En outre, les AcN nouvellement isolés étaient globalement plus neutralisants et de plus large spectre que ceux isolés précédemment, ce qui indique la supériorité de la nouvelle méthode pour l'identification de lignées neutralisantes. Les études structurales en cours permettront d'élucider les épitopes responsables de la neutralisation observée chez ce donneur. L'ensemble de ces résultats pourrait contribuer à la conception d'approches de "vaccinologie inverse", qui représentent à l'heure actuelle un espoir pour la mise au point d'un vaccin contre le VIH
Human Immunodeficiency Virus type 1 (HIV-1) infection remains a major global health concern, with an estimated 37.7 million people living with the virus worldwide and new contaminations above a million cases yearly. Efficient anti-retroviral therapies are available, allowing a sustained relief for infected individuals. These therapeutics have also contributed to a better prevention and helped curb the epidemic, notably in high-income countries. However, a vaccine is still highly awaited for controlling this epidemic, especially in lower-income regions and precarious settings.The protective role of neutralizing antibodies (NAbs) has been unequivocally demonstrated in both animal models of HIV infection and in human settings. Consequently, the development of a B-cell-based vaccine capable of eliciting antibodies (Abs) with the ability to neutralize the majority of circulating viruses, namely broadly NAbs (bNAbs), could be foreseen as an answer to the HIV pandemic.The investigation of bNAb development in HIV-1 elite neutralizers provides valuable insights to inform the design of such vaccines. To date, most of the undertaken studies have relied on conventional single B-cell FACS sorting to isolate bNAbs. In the present study, we have used the Chromium Single Cell Immune Profiling approach to conduct a high-throughput longitudinal single-cell exploration of the B-cell repertoire in an HIV-1 elite neutralizer. Importantly, this novel method enables the use of a much greater number of HIV envelope glycoprotein (Env) baits compared to regular FACS-based Ab isolation studies, providing a more comprehensive view of the anti-Env Ab repertoire. In addition, this approach yields a wealth of information on the nature of the specific Abs identified and the corresponding B-cells.The study enabled the uncovering of the sequence of 12,130 putative HIV Env specific Abs. Antibodies from 39 lineages were produced and tested for neutralization, revealing 21 distinct neutralizing lineages. The results thus demonstrated the ability of the method to explore large antigen-specific Ab repertoires from longitudinal samples. The neutralizing activity of Abs from four neutralizing lineages together recapitulated the serum activity of the donor, achieving neutralization against 62.4 % of a large predictive panel of 126 pseudoviruses. One of these neutralizing Ab lineages was shown to target the gp120 high-mannose patch supersite with great breadth and potency; Abs from this lineage were sensitive to the presence of a glycan in position N332. A single of those Abs achieved most of the neutralization breadth (51.1 %) with a high potency (mean IC50 of 91.1 ng.mL-1). This Ab exhibited a 23 AA-long CDRH3 and 20 % somatic hypermutation (SMH). The lineage showed continuous evolution over 6.5 years of maturation, with observed SHM rates ranging from 2.0 % to 30.6 % for the heavy chain, without any insertions or deletions.Conventional FACS-based sorting was previously used to isolate bNAbs from the same donor. In comparison, the single cell high-throughput approach made possible the isolation of orders of magnitude more Abs. Furthermore, the newly isolated NAbs were overall more potent and broader than those isolated previously, indicating the superiority of the novel method in recovering neutralizing lineages. Ongoing structural studies will elucidate the epitopes responsible for the broad neutralization observed in this donor. Together, the findings may help the design of reverse vaccine approaches, which show promise in the development of an effective AIDS vaccine

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Derby, Nina Rafterman. "Designing immunogens to elicit broadly reactive neutralizing antibodies to the HIV envelope /". Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/9302.

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Penn-Nicholson, Adam Garth. "Characterization and evaluation of approaches to elicit Broadly Reactive Neutralizing Antibodies against HIV-1". Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1205433621.

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Suphaphiphat, Karunasinee. "Anti-viral immune response in the semen of cynomolgus macaques and inhibition of cell to cell transmission by broadly neutralizing antibodies in an SIV/SHIV model of infection SHIV162P3 transmission by semen 1 leukocytes is efficiently 2 inhibited by broadly neutralizing antibodies". Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS599.

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La transmission sexuelle du VIH-1 se fait principalement via du sperme infecté contaminé, contenant à la fois des virions libres et des leucocytes infectés. Les facteurs présents dans le liquide séminal peuvent aussi moduler l’infectivité du sperme et la réponse immunitaire de l’hôte. Ainsi, le macaque infecté par le virus de l’immunodéficience simienne (VIS) sera utilisé comme modèle expérimental afin d’étudier l’infectivité des cellules séminales, les réponses immunitaires anti-virales et évaluer l’effet inhibiteur d’anticorps neutralisant à large spectre (bNAbs) sur la transmission du virus intercellulaire (TVI).Chez les macaques infectés avec le SIVmac251, les réponses immunitaires innées et adaptatives spécifiques du VIS ont été étudiées dans le sperme, en se focalisant sur les réponses T CD8, humorale et sur l’expression des cytokines, chimiokines et facteurs de croissance. L’infection VIS induit l’expression de cytokines pro-inflammatoires et immuno-régulatrices dans le sperme concordant avec une augmentation des cellules activées T CD8+ CD69+ et T CD8+ CXCR3+ CCR5+. Ni les cellules T CD8+ spécifiques du VIS, ni la réponse humorale ne permettent le contrôle de la dissémination du virus dans le sperme. L’absence de contrôle de la réplication virale dans le sperme infecté VIS est associée à une inflammation générale et à une activation immunitaire, pouvant refléter ce qui se produit dans le tractus reproducteur masculin, et qui pourrait mener à l’augmentation de la transmission VIH-1/VIS.De plus, nous avons développé un modèle d’étude in vitro de TVI en utilisant soit la lignée cellulaire TZM-bl, soit des PBMC humains comme cellules cibles, et des splénocytes ou des leucocytes CD45+ du spermes infectés avec le SHIV163P3 comme cellules infectieuses. Ce modèle nous a permis d’évaluer l’inhibition de TVI par des bNAbs. Nous avons testé 4 bNabs de 1ère génération et 8 bNabs de 2nde génération. La combinaison de bNabs de 1ère génération (2F5 + 2G12 + 4E10) permet d’inhiber TVI, alors qu’en combinaison double ou seule, aucune inhibition de la transmission n’est observée. Cependant, les bNabs de 2nde génération peuvent, seules, induire une inhibition de TVI aussi efficacement qu’en combinaison. Ainsi, un bNabs de 2nde génération anti-V3 a été sélectionné afin de tester son effet inhibiteur de TVI dans un modèle in vivo
HIV-1 sexual transmission occurs mostly through contaminated semen, which contains both free virions and infected leukocytes. Moreover, factors in seminal plasma (SP) can influence both semen infectivity and host’s response. Therefore, we used the experimental model of Simian Immunodeficiency Virus (SIV) infection of macaques, to investigate semen cells infectivity and the antiviral immune responses and to evaluate the potency of broadly neutralizing antibodies (bNAbs) to block cell-to-cell virus transmission.In SIVmac251 infected cynomolgus macaques, we investigated SIV-specific innate and adaptive responses in semen, including CD8+ T cell response, humoral response and levels of cytokines, chemokines and growth factors. SIV infection induced pro-inflammatory and immunoregulatory cytokines in semen and a concomitant upregulation of activated CD69+ CD8+ T cells and CCR5+ CXCR3+ CD8+ T cells. Neither SIV-specific CD8+ T-cell responses nor humoral responses controlled seminal viral shedding. Failure to control viral replication in SIV-infected semen is related to a general inflammation and immune activation, which possibly mirrors what happen in the male genital tract and which could lead to enhanced HIV/SIV transmission.Moreover, we developed cell-to-cell transmission assays, using either TZM-bl or human PBMC as target cells and SHIV162P3-infected splenocytes and CD45+ semen leukocytes as donor cells, and evaluated bNAbs-mediated inhibition. The bNAb panel included four 1st generation bNAbs and eight 2nd generation bNAbs. A combination of 1st generation bNAbs (2F5+2G12+4E10) was able to efficiently inhibit CAV transmission, while double combination or single bNAbs showed reduced potency. Of note, individual 2nd generation bNAbs inhibited transmission as efficiently as bNAbs combinations. An anti-V3 bNAb has been selected to evaluate its potential to block cell-to-cell transmission in vivo

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Corti, Davide. "Analysis of the human B cell memory repertoire against infectious pathogens and isolation of broadly neutralizing human monoclonal antibodies /". Bern : [s.n.], 2008. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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Yuan, Tingting y 袁婷婷. "Identification of intermediate antibodies of broadly neutralizing HIV-1 human monoclonal antibody b12 and characterization of variable loops of HIV-1 envelop glycoprotein". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196445.

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Gardner, Matthew Ryan. "Targeting the CD4- and Coreceptor-Binding Sites of the HIV-1 Envelope Glycoprotein". Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11644.

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The HIV-1 envelope glycoprotein, Env, facilitates the translocation of the viral capsid across the cellular membrane. Env is a trimer of hetero-dimers composed of a gp120 subunit and gp41 transmembrane protein. The gp120 subunit binds the primary receptor, CD4, leading to conformational changes of Env that then promote binding to the coreceptor, principally CCR5 or CXCR4. As the sole protein on the surface of the virion, Env is under continuous pressure from the host's antibody response. Two classes of antibodies target the highly conserved receptor-binding sites of gp120: CD4-binding site (CD4bs) and CD4-induced (CD4i) antibodies.

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Cheng, Yuxing. "Elicitation of antibody responses against the HIV-1 gp41 Membrane Proximal External Region (MPER)". Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11427.

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An effective vaccine to protect against HIV-1/AIDS remains elusive due to the extensive mechanisms employed by the HIV-1 virus to evade immune attack. Highly potent broadly neutralizing antibodies isolated from chronically infected individuals, however, show that such relevant antibodies can be naturally produced, implying that their elicitation through vaccination is a realistic possibility. These broadly neutralizing antibodies target different regions on the trimeric spikes formed by three protomers of the envelope (Env) protein. Each Env protein is comprised of the gp120 surface subunit in non-covalent association with the gp41 transmembrane subunit. Four regions have been identified: the CD4 binding site, the V1/V2 segment and the V3/glycan area all on the gp120 subunit as well as the MPER segment on the gp41 subunit. This dissertation focuses on the gp41 MPER segment given its highly conserved amino acid sequence among all HIV-1 clades and viral strain isolates and essential function in Env-mediated fusion and HIV entry. Of note, the MPER segment contains several adjacent epitopes targeted by broadly neutralizing antibodies, suggesting that the immune system is capable of producing neutralizing antibodies against this specific region. Analysis of both clade B and C MPER segments shows them to be L-shaped, consisting of two  helices separated by a hinge. We have found that the hinge region of the MPER segment provides the conformational flexibility necessary for the Env-mediated hemifusion and fusion processes. A significant reduction in virus infectivity is observed when the hinge region is disrupted by introduction of two amino acid mutations that eliminate -helical capping residues and the tandem hinge joints. The importance of the hinge region of the MPER segment is further supported by the action of four MPER-specific neutralizing antibodies 2F5, 4E10, 10E8 and Z13E1. These neutralizing antibodies block virus infection by disrupting MPER hinge-related function.

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Miles, Brodie, Shannon M. Miller y Elizabeth Connick. "CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection". FRONTIERS MEDIA SA, 2016. http://hdl.handle.net/10150/622733.

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T follicular helper cells (T-FH) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in T-FH. Paradoxically, T-FH numbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased T-FH numbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in T-FH function, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in T-FH likely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of T-FH, other mechanisms that have been linked to T-FH deficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance T-FH function in HIV infection include lack of an established phenotype for memory T-FH as well as limited understanding of the relationship between peripheral T-FH and lymphoid tissue T-FH. Interventions to augment T-FH function in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies.

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Hashem, Anwar. "Targeting the Highly Conserved Sequences in Influenza A Virus". Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24058.

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All challenges associated with influenza A viruses including antigenic variation in hemagglutinin (HA) and neuraminidase (NA), the evolving drug resistance and the drawbacks of current vaccines hinder our ability to control this constant threat. Furthermore, gene reassortment as well as the direct transmission of highly pathogenic avian viruses to humans can result in an occasional emergence of novel influenza strains with devastating pandemic potential. Therefore, it is crucial to investigate alternative approaches to better control these viruses and to develop new prophylactic and treatment options. Targeting highly conserved epitopes or antigens among the different subtypes of influenza A virus could offer protection against broad range of influenza viruses, including emerging strains. In my research, I have investigated the potential of broadly neutralizing antibodies against HA and conducted mechanistic study of a prototype vaccine based on the highly conserved nucleoprotein (NP). We recently found that the 14 amino acids of the amino-terminus of the fusion peptide of influenza HA2 subunit is the only universally conserved sequence in all HA subtypes of influenza A and the two lineages of influenza B viruses. Here, I show that universal antibodies targeting this linear sequence in the viral HA (Uni-1 antibodies) can cross-neutralize multiple subtypes of influenza A virus by inhibiting the pH-dependant fusion of viral and cellular membranes. It is noted that the influenza NP is a highly conserved antigen and has the potential to induce heterosubtypic immunity against divergent subtypes of influenza A virus. However, NP-based vaccination only affords weak protective immunity compared to HA. This is mostly due to the non-sterilizing immunity induced by NP. Using CD40 ligand (CD40L), a key regulator of the immune system, as both a targeting ligand and a molecular adjuvant, I show that single immunization with recombinant adenovirus carrying a fused gene encoding the secreted NP-CD40L fusion protein provided robust and long-lasting protection against influenza in normal mice. It enhanced both B-cell and T-cell responses and augmented the role of both NP-specific antibodies and CTLs in protection. Importantly, it afforded effective protection in CD40L and CD4 deficient mice, confirming that the induced protection is CD40L-mediated and CD4+ T cell-independent. The rapid evolution of the influenza A viruses necessitates the development of new alternatives to contain this medically important pathogen. The results of these studies could significantly contribute to future vaccine development and avert the necessity of yearly vaccine updates.

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Libros sobre el tema "Broadly neutralizing antibodies (bNAbs)"

Cox, Josephine H., Stuart Z. Shapiro, Liza Dawson, Cynthia Geppert, Andrew M. Siegel y M. Patricia D’Souza. Vaccines for The Prevention and Treatment of HIV Infection. Editado por Mary Ann Cohen, Jack M. Gorman, Jeffrey M. Jacobson, Paul Volberding y Scott Letendre. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199392742.003.0032.

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While the HIV/AIDS pandemic continues, the overall incidence of HIV infections has fallen through use of antiretroviral therapy (ART) and multiple prevention modalities. To achieve a durable end to the pandemic and avoid the requirement for daily antiretroviral medication over a lifetime, a safe and effective prophylactic vaccine remains essential. This chapter reviews current advances in prophylactic and therapeutic HIV-1 vaccine strategies and the challenges that lie ahead. Recent success in isolation of potent broadly neutralizing antibodies (bnAbs) from infected individuals, the discovery of mechanisms of bnAb induction, and progress in understanding mechanisms of CD8 T-cell killing of HIV-infected cells and the structure of the HIV envelope trimer have opened new strategies for HIV vaccine design. On the therapeutic front, the persistence of HIV reservoirs remains a formidable obstacle to achieving sustained virological remission in HIV-infected individuals after ART is discontinued. Development of a new generation of immune-based therapeutic agents might contribute to a curative intervention. The chapter closes with an overview of ethical challenges in vaccine development and clinical testing.

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Schommers, Philipp, Harry Gristick, Marit J. Van Gils y Kshitij Wagh, eds. Novel Concepts in Using Broadly Neutralizing Antibodies for HIV-1 Treatment and Prevention. Frontiers Media SA, 2022. http://dx.doi.org/10.3389/978-2-88974-305-6.

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Capítulos de libros sobre el tema "Broadly neutralizing antibodies (bNAbs)"

Wu, Xueling. "HIV Broadly Neutralizing Antibodies: VRC01 and Beyond". En HIV Vaccines and Cure, 53–72. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-0484-2_3.

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Zhou, Tongqing y Kai Xu. "Structural Features of Broadly Neutralizing Antibodies and Rational Design of Vaccine". En HIV Vaccines and Cure, 73–95. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-0484-2_4.

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Pauthner, Matthias G. y Lars Hangartner. "Broadly Neutralizing Antibodies to Highly Antigenically Variable Viruses as Templates for Vaccine Design". En Current Topics in Microbiology and Immunology, 31–87. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/82_2020_221.

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Zhang, Mei-Yun y Dimiter S. Dimitrov. "Sequential Antigen Panning for Selection of Broadly Cross-Reactive HIV-1-Neutralizing Human Monoclonal Antibodies". En Methods in Molecular Biology, 143–54. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-60327-302-2_11.

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Van Regenmortel, Marc H. V. "Why Does the Molecular Structure of Broadly Neutralizing Monoclonal Antibodies Isolated from Individuals Infected with HIV-1 Not Inform the Rational Design of an HIV-1 Vaccine?" En HIV/AIDS: Immunochemistry, Reductionism and Vaccine Design, 221–28. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-32459-9_19.

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Morris, L. y T. A. Moody. "Broadly Neutralizing Antibodies". En Human Vaccines, 3–21. Elsevier, 2017. http://dx.doi.org/10.1016/b978-0-12-802302-0.00012-1.

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Mohamed, Yehia. "The Future of HIV Vaccine Development, Learned Lessons from COVID-19 Pandemic". En New Topics in Vaccine Development [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.114355.

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With nearly 13 million new HIV infections in 2022, it is imperative that as many preventive options be available to those most at risk. Without doubt, an effective vaccine would be a game changer, and despite the disappointments and challenges, the development of an effective HIV vaccine should remain a priority. The past few years have been tough for HIV vaccine research, with several high-profile trials being stopped early and others having negative results. With every setback, however, there are lessons to be learned. Neutralizing antibodies (bnAbs), either by giving infusions of bnAbs or by eliciting the immune system to generate its own, are the main emphasis. The focus seems to be on the development of mRNA vaccine approaches using technologies pioneered during the development of COVID-19 vaccines. mRNA platforms are being used in many of the current phase 1 vaccine studies. The quick development of mRNA vaccines for COVID-19 will likely not be repeated with HIV, which is a much more formidable immunological foe than SARS-CoV-2. However, it is reassuring that vaccine trials are moving to sub-Saharan Africa, and large mRNA manufacturing facilities are being planned for the region.

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Ni, Fengyun y Qinghua Wang. "Stem-specific Broadly Neutralizing Antibodies of Influenza Virus Hemagglutinin". En Influenza: Current Research, 1–16. Caister Academic Press, 2016. http://dx.doi.org/10.21775/9781910190432.01.

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Haynes, Barton F., Kevin O. Saunders, Garnett Kelsoe, John R. Mascola y Gary J. Nabel. "The Cellular and Molecular Biology of HIV-1 Broadly Neutralizing Antibodies". En Molecular Biology of B Cells, 441–61. Elsevier, 2015. http://dx.doi.org/10.1016/b978-0-12-397933-9.00024-2.

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Mallard, Bonnie, Mehdi Emam, Shannon Cartwright, Tess Altvater-Hughes, Alexandra Livernois, Lauri Wagter-Lesperance, Douglas C. Hodgins et al. "Advances in understanding immune response in dairy cattle". En Improving dairy herd health Improving, 121–62. Burleigh Dodds Science Publishing, 2021. http://dx.doi.org/10.19103/as.2020.0086.06.

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From the beginning, cattle have made important contributions to the field of immunology, including the development of the first Mycobacterium bovis BCG vaccine for human tuberculosis in 1921. In 1981 the first report of a biosynthesized polypeptide vaccine against Foot and Mouth Disease Virus (FMDV) using the VP3 protein expressed in Escherichia coli (E. coli) was made for cattle. Cattle also possess a substantial proportion of T cells expressing the γδ T-cell receptor which helped to elucidate the role of these unique cells in host defence. More recently, it was discovered that cattle produce antibodies with ultra-long Complementarity Determining Region (CDR) - 3. This seminal finding has allowed the production of bovine therapeutic broadly neutralizing antibodies with ultra-long CDRs to passively treat various virial infections in humans and play a key role in protecting cattle. This chapter will review advances in bovine immunology, particularly as it relates to dairy cattle.

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Actas de conferencias sobre el tema "Broadly neutralizing antibodies (bNAbs)"

Morton, Scott P. y Joshua L. Phillips. "pH Dependent Binding Energies of Broadly Neutralizing Antibodies". En 2021 IEEE International Conference on Bioinformatics and Biomedicine (BIBM). IEEE, 2021. http://dx.doi.org/10.1109/bibm52615.2021.9669511.

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Solodkov, P. P., T. N. Belovezhets, A. N. Chikaev, K. O. Baranov, S. V. Kulemzin, A. A. Gorchakov, S. V. Guselnikov et al. "SINGLE DOMAIN LLAMA ANTIBODIES BROADLY NEUTRALIZING SARS-COV-2 VARIANTS". En X Международная конференция молодых ученых: биоинформатиков, биотехнологов, биофизиков, вирусологов и молекулярных биологов — 2023. Novosibirsk State University, 2023. http://dx.doi.org/10.25205/978-5-4437-1526-1-127.

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The late stage of the COVID-19 pandemic is marked by the appearance of mutant variants of SARS-CoV-2 that can escape the immunity against the Wuhan virus. In this work, we report on the development of a panel of antiviral agents — single-domain antibodies that recognize independent epitopes of the SARS-CoV-2 S protein. Four antibodies from this panel neutralize a wide range of virus variants, including the most common ones at present: XBB.1.5 and XBB.1.16.

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Flyak, Andrew I., Stormy Ruiz, Michelle Colbert, Tiffany Luong, James E. Crowe, Justin R. Bailey y Pamela J. Bjorkman. "Abstract B109: Broadly neutralizing antibodies against HCV use a CDRH3 disulfide motif to recognize an E2 glycoprotein site that can be targeted for vaccine design". En Abstracts: Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; September 30 - October 3, 2018; New York, NY. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/2326-6074.cricimteatiaacr18-b109.

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