Tesis sobre el tema "Broadly neutralizing antibodies (bNAbs)"
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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.
Texto completoHuman 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
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.
Texto completoPenn-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.
Texto completoSuphaphiphat, 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.
Texto completoHIV-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
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.
Texto completoYuan, 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.
Texto completoGardner, 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.
Texto completoCheng, 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.
Texto completoMiles, 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.
Texto completoHashem, Anwar. "Targeting the Highly Conserved Sequences in Influenza A Virus". Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24058.
Texto completoRousset, Claire. "Coévolution entre les glycoprotéines d'enveloppe du VIH et les anticorps neutralisants à large spectre ciblant la région du glycane N332". Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAV071/document.
Texto completoHIV has been the cause of the AIDS pandemic since the 1980s. With over a million new infections each year, a prophylactic vaccine is needed to stop the virus spread. Among vaccine strategies, the induction of broadly neutralizing antibodies is one of the most promising, as they could protect against infection by the huge genetic diversity of circulating HIV strains. To date, no immunogen has induced such antibodies, but they have been isolated from HIV infected people. Indeed, a small fraction of infected individuals eventually develops broadly neutralizing antibodies that target vulnerable and conserved sites of the envelope glycoprotein. The region of the high-mannose patch, centred around a glycan at position N332 of gp120, is the most frequently targeted, and is therefore attractive from a vaccination standpoint.In order to better understand how antibodies targeting the high-mannose patch develop, we studied a donor selected from the International AIDS Vaccine Initiative Protocol C cohort with exceptional serum neutralizing activity. We isolated two antibody lineages targeting the N332 region from this individual's blood cells, which we characterized for their neutralizing activity and mapped their epitope. We also mapped the paratope of an antibody lineage from another Protocol C donor, also targeting the N332 region. Our results show the great diversity of solutions to achieve broad neutralization against this region. Lineage studies, as we have undertaken, provide an understanding of how antibody-virus coevolution leads to the selection of broadly neutralizing antibodies. The ultimate goal is to use this knowledge to develop immunogens and immunization protocols, to induce specific antibody lineage and drive their evolution towards broad neutralization
Madzorera, Vimbai Sharon. "Engineering HIV viral variants as immunogens to stimulate Broadly Neutralizing Antibodies". Thesis, 2018. https://hdl.handle.net/10539/25326.
Texto completoSouthern Africa is currently the most affected region of the world in terms of the HIV/AIDS pandemic and despite decades of research into this virus, a vaccine that is adequately effective is yet to be developed. However, it is widely believed that broadly neutralizing antibodies (bNAbs) are likely to be required for protection. Eliciting bNAbs by vaccination has been challenging for several reasons, one of which is the failure of most viral proteins to bind the germline versions of bNAbs (bNAb precursors). For vaccine design, it will be necessary to either select or engineer suitable immunogens that bind the inferred bNAb precursors in vitro, which is the first step in driving such responses towards breadth. This study focused on an unusual set of six previously identified viral escape mutations (collectively referred to as CS-Mut) that enhance neutralization by bNAbs to the membrane proximal external region (MPER). These mutations were used to engineer and test a variety of viral constructs for their potential as vaccine candidates. We first tested the effect of each individual cleavage site mutation on viral entry and MPER exposure. We showed that individual mutations resulted in reduced viral entry potential, but not to the same extent as all six mutations combined in the CS-Mut. We next tested the effect of the individual mutations on neutralization by MPER bNAbs. We showed that most of the single mutations enhanced viral sensitivity to MPER bNAbs, with three of the six mutations most promising in terms of MPER exposure. However, the MPER enhancement was less marked than the combined set of six mutations, suggesting further improvement was needed. We therefore next combined the three most promising mutations into a single construct and showed that enhancement of MPER sensitivity was improved for this triple mutant compared to the individual mutants. Indeed, for some MPER bNAbs, the triple mutant was more sensitive to MPER bNAbs than the matched virus containing all six mutations. Moreover, the entry capacity of the triple mutant was significantly improved over the six mutant construct, making it more amenable to incorporation into virus-like particles for vaccine design. Lastly, we engineered dual germline targeting immunogens by simultaneously adding the MPER enhancing mutations to five viruses that were previously shown to have a high probability of binding V2 bNAb precursors (V2 “special strains”). The “special strain” CS-Mut viruses exhibited varying degrees of reduction in viral entry potential, with infectivity abrogated for two. For the remaining three “special strain” CS-Mut viruses, enhancement in MPER sensitivity was observed. Increased sensitivity was largely specific for bNAbs targeting the MPER epitope or interface, as bNAbs and plasma to other viral epitopes showed no enhanced neutralization. However, despite enhanced sensitivity to mature MPER bNAbs, no neutralization was observed using germline reverted MPER bNAbs, the best available approximate of MPER precursors. In conclusion, the cleavage site mutations resulted in favorable exposure of the MPER epitope, a trait that is promising for immunogen design. However, the fitness cost that results from the addition of the cleavage site mutations is problematic for use of these constructs in vaccines using virus-like particles. In future studies, a balance between viral entry potential and enhancement of MPER neutralization needs to be determined to optimize immunogen candidates. The CAP256 SU CS-Mut construct showed promise as a dual germline targeting immunogen, exhibiting limited reduction in entry potential while favorably exposing the MPER epitope, with minimal disruption to the native envelope trimer structure.
LG2018
Scheepers, Cathrine. "Host factors and broadly neutralizing antibodies in South African women infected with HIV-1 subtype C". Thesis, 2016. http://hdl.handle.net/10539/19680.
Texto completoBroadly neutralizing antibodies are capable of neutralizing a large number of HIV-1 strains and have shown to be protective against infection in non-human primate models. These antibodies are likely to play an important role in an effective vaccine against HIV. Eliciting them by vaccination has thus far been unsuccessful and their unusual features such as long CDHR3 lengths and high levels of somatic hypermutation make this a particularly challenging task. Approximately 15-30% of chronically HIV-1 infected individuals develop these types of antibodies but an understanding of the underlying mechanisms is limited. The aim of this study, therefore, was to investigate host factors associated with the development of broadly neutralizing antibodies in HIV-1 subtype C infected individuals. In particular we analysed genetic variation of the genes encoding the variable region of antibodies, the evolution of an HIV-1 specific antibody lineage and glycan-binding profiles of serum antibodies. The human heavy chain variable region genes (IGHV) are the largest and most variable of all human immunoglobulin genes and encode the major antigen-binding region. These genes are divided into seven subgroups, each subgroup contains numerous genes and alleles. Using genomic DNA from 28 HIV-1 subtype C infected individuals we performed next generation sequencing using both Illumina MiSeq and Roche 454 technologies. Included were 13 individuals who developed broadly neutralizing antibodies, 13 who did not despite chronic HIV-1 infection and two intermediate neutralizers. We found no genetic differences in the IGHV genes between these two groups. However, we identified 85 novel alleles and 38 alleles that had previously only been observed in rearranged antibody sequences. Of these alleles, eight were used by functional antibodies, two of which were HIV-1 specific. This study highlights the importance of a fully comprehensive database for inferring germline gene usage and the unmutated common ancestors of antibody lineages. In addition it showed that everyone has the same genetic potential of developing broadly neutralizing antibodies, which has positive implications for vaccine development. A number of studies have demonstrated the importance of strain-specific antibodies in the development of broadly neutralizing antibodies. In addition to being the forerunners of broadly neutralizing antibodies, strain-specific antibodies can help shape the viral populations that elicit different broadly neutralizing antibody lineages. We therefore studied the evolution of a strain-specific HIV antibody lineage (CAP88-CH06) in an individual who failed to develop neutralization breadth even after 5 years of infection, to understand why some strain-specific antibodies remain limited to autologous viruses. CAP88-CH06 was previously isolated as an IgA1 antibody using the IGHV4-39 gene with 8.8% divergence from donor CAP88 at 34 weeks post-infection, which mapped to the C3- V4 region of gp120. IgA and IgG antibodies using the same germline IGHV were sequenced on an Illumina MiSeq from 5 to 121 weeks post-infection. IgA sequences identical to that of the fully matured antibody with 8.8% divergence were detected from early infection and throughout until after 2 years, well after viral escape. This was consistent with plasma neutralization of the C3-V4 region within CAP88. However, very little evidence of evolution was seen within the IgA sequences. A group of related IgG sequences were also identified between 11 and 34 weeks but not at other time-points. Interestingly, within the 11 week transcripts we identified an identical sequence as both an IgA and IgG isotype, which likely gave rise to these transient IgG antibodies. The lack of neutralization breadth in this individual could therefore be the result of both limited evolution of the IgA isotype and well as the disappearance of the IgG isotype. The HIV envelope is surrounded by glycans, known as the glycan shield. These glycans contribute towards the structural integrity of the envelope and serve as protection against immune responses to conserved regions. However, glycans often form targets for broadly neutralizing antibodies. Thus we studied the glycan-binding profiles of HIVnegative and HIV-positive individuals (including 12 individuals who develop broadly neutralizing antibodies and 13 who did not despite chronic infection) to determine whether glycan-binding was specific to individuals who develop broadly neutralizing antibodies. Longitudinal samples were taken yearly for three years from all 47 individuals and their serum IgG levels were tested on glycan microarrays. We observed fluctuations in glycanbinding over time within the HIV-negative individuals and these were used to establish baseline values. The HIV-positive individuals were found to have elevated levels of antibodies targeting high mannose N-linked glycans, Tn-peptides and glycolipids during infection. Binding to Tn-peptides and glycolipids were elevated throughout infection, whereas high mannose N-linked glycans were elevated from 2-3 years post-infection. We observed no differences in these glycans between the individuals who developed broadly neutralizing antibodies compared to those who did not despite chronic HIV infection. This data suggests that the elevated levels of glycan-binding serum antibodies were a consequence of infection rather than specific to broadly neutralizing antibodies. Since glycan-binding antibodies against Tn-peptides and glycolipids were detected earlier than high mannose N-linked glycans and antibodies targeting these glycans were elevated during infection, they might warrant further investigation with respect to immunogen design. Collectively this study has contributed to a greater understanding of the role of various host factors in the development of broadly neutralizing antibodies to HIV. This includes showing that there were no differences in the IGHV genes between individuals who did and did not develop broadly neutralizing antibodies as well as providing a wealth of new data on human antibody genes that will have benefits beyond the field of HIV. Furthermore our study has reinforced the essential role of somatic hypermutation in developing neutralization breadth and the need for further co-evolution studies on strainspecific lineages to understand this roadblock. Finally our study using glycan arrays has highlighted that glycan-binding antibodies are induced in all HIV-infected individuals even though only a minority go on to develop broadly neutralizing antibodies. Overall these data suggest that all humans have the ability to develop broadly neutralizing antibodies but a vaccine capable of eliciting such protective responses remains a major hurdle.
Wierzbicka, Marta. "Investigation of a Putative Secondary Binding Site between the Broadly Neutralizing Monoclonal anti-HIV-1 Antibody and its Antigen gp41". Thesis, 2010. http://hdl.handle.net/1807/25513.
Texto completoRegistre, Ludy. "Examination of the role of envelope directed antibodies on co-receptor usage in HIV-1B infection". Thesis, 2018. https://hdl.handle.net/2144/29958.
Texto completo2020-06-12T00:00:00Z
Wu, Ji Hung y 吳季鴻. "Influenza virus-like particles by glycan masking and unmasking of hemagglutinin antigens to induce broadly neutralizing antibodies against H5N1 avian influenza viruses". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/mp5km4.
Texto completoNiessl, Julia. "Modulation of HIV-specific T cell responses during standard antiretroviral treatment and immunotherapy". Thesis, 2020. http://hdl.handle.net/1866/24606.
Texto completoOnly a small fraction of individuals infected with the human immunodeficiency virus (HIV) develops effective immune responses able to control the virus. In most individuals, the virus escapes the antiviral immune response and HIV-specific CD8+ T cell responses become exhausted. Untreated progressive HIV infection also leads to alterations in HIV-specific CD4+ T cells. This includes increased expression of co-inhibitory receptors and skewing towards a T follicular helper cell (Tfh) signature. Antiretroviral therapy (ART) is highly effective in controlling the HIV viral load at undetectable levels in the plasma. However, ART does not represent a cure as the virus integrates into the genome of infected cells from where the virus rebounds once ART is stopped. This demonstrates that the HIV-specific T cell immunity is not restored. However, the changes that are introduced during progressive infection and that are maintained after viral suppression with ART are poorly known. Broadly neutralizing antibodies (bNAbs) represent a potential alternative to ART. In addition to virus neutralization and unlike ART, bNAbs to do not limit HIV antigen availability and can engage the immune system. bNAb administration elicited adaptive immune responses that were associated with long-lasting viral control in a simian animal model but this has not been established in HIV-infected individuals. In this thesis, we therefore proceeded to study the modulation of HIV-specific T cell responses during standard ART and after an immunotherapeutic intervention using bNAbs. The first objective was to better understand persistent modulation of HIV-specific CD4+ T cell responses in ART-treated individuals. Our results demonstrated the persistent expansion of HIV-specific Tfh cell responses with multiple phenotypic and functional features that differed from Tfh cells specific for comparative viral antigens (cytomegalovirus, hepatitis B virus). These features were induced during chronic untreated HIV infection, persisted during ART and correlated with the translation-competent HIV reservoir. This suggests that persistent HIV antigen expression, despite effective ART, maintains these altered immunological features specifically for Tfh responses. For the second objective, we characterized changes in the HIV-specific CD8+ and CD4+ T cell immunity after bNAb treatment and analytical treatment interruption (ATI). For this, we used samples obtained from participants enrolled in a clinical phase Ib study that received combined infusion of bNAbs 10-1074 and 3BNC117 and demonstrated prolonged viral suppression after ATI. In these individuals, we detected an increase of HIV-specific CD8+ and CD4+ T cell responses during ART interruption when compared to baseline. Increased T cell responses were due to both expansion of pre-existing responses and the emergence of responses to new epitopes. In contrast, HIV-specific T cell responses remained unchanged in ART-treated individuals who did not receive bNAb infusions. This suggests that bNAb treatment and ATI is associated with increased HIV-specific T cell immunity while viral suppression is maintained. Together our results contribute to a better understanding of HIV-specific T cell responses during ART and immunotherapy treatment. Our findings may help to develop more effective HIV treatment strategies to improve the host’s immune system so that HIV can be controlled without the need for ART.