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Harnessing Antibody-Dependant Cellular Cytotoxicity Against HIV-1-Infected Cells.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Harnessing Antibody-Dependant Cellular Cytotoxicity Against HIV-1-Infected Cells./
作者:	Anand, Sai Priya.
面頁冊數:	1 online resource (263 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-05, Section: B.
Contained By:	Dissertations Abstracts International84-05B.
標題:	Infections. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30157747click for full text (PQDT)
ISBN:	9798352989531

Harnessing Antibody-Dependant Cellular Cytotoxicity Against HIV-1-Infected Cells.
Anand, Sai Priya.

Harnessing Antibody-Dependant Cellular Cytotoxicity Against HIV-1-Infected Cells. - 1 online resource (263 pages)

Source: Dissertations Abstracts International, Volume: 84-05, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2022.

Includes bibliographical references

In the absence of an efficient vaccine and with current antiretroviral therapies unable to eradicate the virus, HIV/AIDS remains a serious global public health concern. The successful elimination of the long-lived latent cellular reservoir poses a significant hurdle for cure strategies. Novel therapeutic interventions currently being explored include antibody-based immunotherapy. The HIV-1 envelope glycoproteins (Env) represent the only antigen exposed at the surface of infected cells and thus, represent a unique target for intervention. Env of most clinical HIV-1 isolates assumes a 'closed' conformation, preventing the binding of non-neutralizing antibodies (nNAbs), which preferentially bind when Env is 'open'. While nNAbs are naturally present in sera from infected individuals, broadly neutralizing antibodies (bNAbs) that recognize the 'closed' conformation are elicited only in a small proportion of infected individuals. Nevertheless, anti-Env antibodies can mediate Fc-effector functions via interactions between their Fc domains and IgG Fc receptors (FcγR), including antibody-dependent cellular cytotoxicity (ADCC). The passive administration of bNAbs can control disease progression in vivo and their capacity to eliminate infected cells is currently being investigated in ongoing human clinical trials. Another strategy to eliminate infected cells includes the use of small CD4 mimetics (CD4mc) to 'open' the Env and facilitate the recognition by nNAbs. In this thesis, we studied three different strategies to harness Fc-effector activities of both bNAbs and nNAbs to eliminate HIV-1-infected cells.Two families of nNAbs predominant in HIV+ sera were shown to exert ADCC activity in the presence of CD4mc. Our first objective was to understand how these two classes of nNAbs cooperate for Fc-effector functionality and we observed that both their Fc regions act in concert to engage FcγRIIIa and mediate ADCC.HIV-1 is a master of immune evasion and increasing evidence indicates that it has developed several mechanisms to avoid the premature recognition of its Env. In this thesis, we uncover a new evasion mechanism, wherein Env is internalized upon the binding by antibodies recognizing its 'closed' conformation. This new understanding led us to test the hypothesis that blocking antibody-induced Env internalization could enhance Fc-effector responses. We found that blocking dynamin function translates into a higher susceptibility of infected cells to ADCC, exploiting another approach to target the viral reservoir.Lastly, to take advantage of the transient formation of antibody-Env immune complexes on the cell surface, we explored the impact of enhancing Fc functionality by glycan modifications. Using Nicotiana benthamiana to generate Fc-glycovariants of a clinically relevant bNAb, we found that afucosylated antibodies, independent of their galactosylation status, demonstrated augmented FcγRIIIa interaction and ADCC activity. Our results with plant-produced antibodies confirms the growing interest in affordable biologic production platforms for antibody-based treatments against infected cells.Altogether, findings from this thesis highlight important ways that Fc-mediated effector functions of both bNAbs and nnAbs are modulated and can inform the design of immunotherapies against HIV-1-infected cells. With additional studies to evaluate the potential of these factors in controlling HIV-1 replication in vivo, these results could potentially be applied towards strategies targeting latently infected cells to decrease the viral reservoir.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798352989531Subjects--Topical Terms:

1621997
Infections.
Index Terms--Genre/Form:

542853
Electronic books.

Harnessing Antibody-Dependant Cellular Cytotoxicity Against HIV-1-Infected Cells.
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520 $a In the absence of an efficient vaccine and with current antiretroviral therapies unable to eradicate the virus, HIV/AIDS remains a serious global public health concern. The successful elimination of the long-lived latent cellular reservoir poses a significant hurdle for cure strategies. Novel therapeutic interventions currently being explored include antibody-based immunotherapy. The HIV-1 envelope glycoproteins (Env) represent the only antigen exposed at the surface of infected cells and thus, represent a unique target for intervention. Env of most clinical HIV-1 isolates assumes a 'closed' conformation, preventing the binding of non-neutralizing antibodies (nNAbs), which preferentially bind when Env is 'open'. While nNAbs are naturally present in sera from infected individuals, broadly neutralizing antibodies (bNAbs) that recognize the 'closed' conformation are elicited only in a small proportion of infected individuals. Nevertheless, anti-Env antibodies can mediate Fc-effector functions via interactions between their Fc domains and IgG Fc receptors (FcγR), including antibody-dependent cellular cytotoxicity (ADCC). The passive administration of bNAbs can control disease progression in vivo and their capacity to eliminate infected cells is currently being investigated in ongoing human clinical trials. Another strategy to eliminate infected cells includes the use of small CD4 mimetics (CD4mc) to 'open' the Env and facilitate the recognition by nNAbs. In this thesis, we studied three different strategies to harness Fc-effector activities of both bNAbs and nNAbs to eliminate HIV-1-infected cells.Two families of nNAbs predominant in HIV+ sera were shown to exert ADCC activity in the presence of CD4mc. Our first objective was to understand how these two classes of nNAbs cooperate for Fc-effector functionality and we observed that both their Fc regions act in concert to engage FcγRIIIa and mediate ADCC.HIV-1 is a master of immune evasion and increasing evidence indicates that it has developed several mechanisms to avoid the premature recognition of its Env. In this thesis, we uncover a new evasion mechanism, wherein Env is internalized upon the binding by antibodies recognizing its 'closed' conformation. This new understanding led us to test the hypothesis that blocking antibody-induced Env internalization could enhance Fc-effector responses. We found that blocking dynamin function translates into a higher susceptibility of infected cells to ADCC, exploiting another approach to target the viral reservoir.Lastly, to take advantage of the transient formation of antibody-Env immune complexes on the cell surface, we explored the impact of enhancing Fc functionality by glycan modifications. Using Nicotiana benthamiana to generate Fc-glycovariants of a clinically relevant bNAb, we found that afucosylated antibodies, independent of their galactosylation status, demonstrated augmented FcγRIIIa interaction and ADCC activity. Our results with plant-produced antibodies confirms the growing interest in affordable biologic production platforms for antibody-based treatments against infected cells.Altogether, findings from this thesis highlight important ways that Fc-mediated effector functions of both bNAbs and nnAbs are modulated and can inform the design of immunotherapies against HIV-1-infected cells. With additional studies to evaluate the potential of these factors in controlling HIV-1 replication in vivo, these results could potentially be applied towards strategies targeting latently infected cells to decrease the viral reservoir.
520 $a En l'absence d'un vaccin efficace et avec les therapies antiretrovirales actuelles incapables d'eradiquer le virus, le VIH/SIDA reste un grave probleme de sante publique au niveau mondial. L'elimination du reservoir cellulaire latent a longue duree de vie constitue le plus grand obstacle pour les strategies de guerison. Parmi les nouvelles interventions therapeutiques actuellement a l'etude figurent les immunotherapies a base d'anticorps. Les glycoproteines de l'enveloppe du VIH-1 (Env) representent le seul antigene expose a la surface des cellules infectees et constituent donc une cible unique pour une intervention. L'Env de la plupart des isolats cliniques du VIH-1 adopte une conformation 'fermee', empechant la liaison des anticorps non neutralisants (nNAbs), qui se fixent de preference lorsque Env est 'ouverte'. Alors que les nNAbs sont naturellement presents dans le serum des personnes infectees, les anticorps neutralisants a large spectre (bNAbs) qui reconnaissent la conformation 'fermee' ne sont produits que chez une tres faible proportion de personnes infectees. Neanmoins, les anticorps anti-Env peuvent medier des fonctions effectrices via l'interaction entre leur domaine Fc et les recepteurs Fc (FcγR), y compris la cytotoxicite cellulaire dependante des anticorps (ADCC). L'administration passive de bNAbs peut controler la progression de la maladie in vivo et leur capacite a eliminer les cellules infectees est actuellement etudiee dans des essais cliniques. Une autre strategie pour eliminer les cellules infectees inclut l'utilisation de mimetiques moleculaires de CD4 (CD4mc) pour 'ouvrir' Env et faciliter sa reconnaissance par les nNAbs. Nous avons etudie trois strategies pour exploiter l'activite effectrice des bNAbs et des nNAbs afin d'eliminer les cellules infectees par le VIH-1. Deux familles de nNAbs predominantes dans les serums VIH+, ont ete montrees comme exercant une activite ADCC en presence de CD4mc. Notre premier objectif etait de comprendre comment ces deux classes de nNAbs cooperent pour l'activite effectrice et nous avons observe que leurs deux regions Fc agissent de concert pour engager le recepteur FcγRIIIa et medier ADCC. Le VIH-1 est un maitre de l'evasion immunitaire et il y a de plus en plus de preuves montrant qu'il a developpe plusieurs mecanismes pour eviter la reconnaissance prematuree d'Env. Dans cette these, nous avons identifie un nouveau mecanisme d'evasion, dans lequel Env est internalise lors de la liaison par des anticorps reconnaissant sa conformation 'fermee'. Cette nouvelle comprehension nous a conduit a tester l'hypothese selon laquelle le blocage de l'internalisation de l'Env induite par les anticorps pourrait ameliorer les reponses effectrices. Nous avons constate que le blocage de la fonction de la dynamine se traduit par une plus grande susceptibilite des cellules infectees a l'ADCC, exploitant ainsi une autre approche pour cibler le reservoir. Enfin, pour prendre avantage de la formation transitoire de complexes immuns anticorps-Env a la surface des cellules, nous avons explore l'impact de l'amelioration de la fonctionnalite des domaines Fc par des modifications de glycans. En utilisant Nicotiana benthamiana pour generer des glycovariants d'un bNAb ayant un potentiel clinique, nous avons decouvert que les anticorps afucosyles, independamment de leur statut de galactosylation, demontraient une interaction avec le FcγRIIIa et une activite ADCC accrues. Nos resultats avec les anticorps produits par des plantes confirment l'interet croissant pour les plateformes de production biologique abordables pour les traitements a base d'anticorps contre les cellules infectees.Dans l'ensemble, les resultats de cette these mettent en evidence des facons importantes de moduler les fonctions effectrices mediees par le Fc des bNAbs et des nnAbs et peuvent informer la conception d'immunotherapies contre les cellules infectees par le VIH-1. Avec des etudes supplementaires pour evaluer le potentiel de ces facteurs dans le controle de la replication du VIH-1 in vivo, ces resultats pourraient potentiellement etre appliques a des strategies ciblant les cellules infectees de facon latente pour diminuer le reservoir viral.
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