Novel HIV-1 Env trimer probes for efficient isolation of broadly neutralizing antibodies

用于有效分离广泛中和抗体的新型 HIV-1 Env 三聚体探针

• 批准号: 10080301
• 负责人: Xueling Wu
• 金额: $ 49.72万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-19 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080301
• 关键词: Novel; HIV; Env; trimer; probes

SUMMARY HIV-1 envelope (Env) probes are key to the isolation of broadly neutralizing antibodies (bnAbs) and the HIV-1 bnAbs are particularly useful to inform and guide Env immunogen design. As current probes and methods have limitations that hinder efficient bnAb isolation from large numbers of individuals, we propose to develop novel VSV-based probes to display dense HIV-1 Env trimers on the surface to isolate bnAbs. We hypothesize that properly constructed gp140.VSV probes provide a powerful tool for bnAb isolation and allow efficient identification of bnAbs from a large number (n>50) of clade-B and non-B clade infected individuals, some with undefined novel epitopes. To test this hypothesis, we collaborate with Dr. Andres Finzi to study samples from a clade-B infected cohort based in Montreal, Canada, and with Dr. Phillipe Nyambi to study samples from a multi-clade infected cohort based in Yaounde, Cameroon. We have screened 111 Montreal and 260 Cameroon plasmas and identified 32 and 13 donors with bnAb activity, respectively. We propose to 1) construct, characterize, and optimize gp140.VSV probes for various clade-B and non-B Envs, 2) apply gp140.VSV probes to isolate bnAbs from >50 clade-B and non-B clade infected broad neutralizers, and 3) determine the epitopes of newly isolated bnAbs and define new bnAb genetic compositions. In pilot experiments, we generated a gp140.VSV probe displaying the HIV-1 AD17 Env trimer on the surface; using this probe, we recovered two distinct and novel bnAbs from a clade-B infected Montreal donor. This preliminary result supports our hypothesis and provides a proof-of-concept that the gp140.VSV probe can lead to the isolation of novel bnAbs. We anticipate that >50 new bnAbs will be identified by this probing method and some of them will define new Env targets and bnAb genetic compositions. The addition of these bnAbs will complement others to expand the bnAb repertoire and advance our understanding of the bnAb epitopes and genetic compositions, thus facilitating Env immunogen design and post-immunization analysis.

总结 HIV-1包膜（Env）探针是分离广泛中和抗体（bnAb）和抗HIV-1抗体的关键。 HIV-1 bnAb对于告知和指导Env免疫原设计特别有用。作为电流探头和 方法具有阻碍从大量个体中有效分离bnAb的局限性，我们 建议开发新型的基于VSV的探针，以在表面上显示密集的HIV-1 Env三聚体， bnAbs。我们假设，正确构建的gp140.VSV探针为bnAb提供了一个强大的工具， 分离并允许从大量（n>50）进化枝B和非B中有效鉴定bnAb 进化枝感染的个体，一些具有未定义的新表位。为了验证这一假设，我们 与Andres Finzi博士一起研究来自加拿大蒙特利尔的B分支感染队列的样本， 与Phillipe Nyambi博士一起研究来自雅温得多分支感染队列的样本， 喀麦隆.我们筛选了111个蒙特利尔和260个喀麦隆血浆， bnAb活性的供体。我们建议1）构建、表征和优化 用于各种进化枝B和非B Env的gp140.VSV探针，2）应用gp140.VSV探针以分离bnAb 从>50个进化枝-B和非-B进化枝感染的广泛中和剂，和3）确定新的 分离的bnAb并定义新的bnAb遗传组成。在试点实验中，我们生成了一个 gp140.VSV探针在表面上展示HIV-1 AD 17 Env三聚体;使用该探针，我们回收了 来自进化枝B感染的蒙特利尔供体的两种不同且新颖的bnAb。这一初步结果支持了我们的 VSV探针可以导致新的分离，并且提供了gp140.VSV探针可以导致新的分离的概念验证。 bnAbs。我们预计，通过这种探测方法将鉴定出>50种新的bnAb，其中一些将 定义新的Env靶标和bnAb遗传组成。这些bnAb的加入将补充 其他人扩大了bnAb库，并推进了我们对bnAb表位和遗传学的理解。 本发明提供了一种用于制备Env免疫原组合物的方法，从而促进Env免疫原设计和免疫后分析。

项目成果

A single dose of the SARS-CoV-2 vaccine BNT162b2 elicits Fc-mediated antibody effector functions and T cell responses.

• DOI: 10.1016/j.chom.2021.06.001
• 发表时间: 2021-07-14
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Tauzin A;Nayrac M;Benlarbi M;Gong SY;Gasser R;Beaudoin-Bussières G;Brassard N;Laumaea A;Vézina D;Prévost J;Anand SP;Bourassa C;Gendron-Lepage G;Medjahed H;Goyette G;Niessl J;Tastet O;Gokool L;Morrisseau C;Arlotto P;Stamatatos L;McGuire AT;Larochelle C;Uchil P;Lu M;Mothes W;De Serres G;Moreira S;Roger M;Richard J;Martel-Laferrière V;Duerr R;Tremblay C;Kaufmann DE;Finzi A
• 通讯作者: Finzi A

SARS-CoV-2 Portrayed against HIV: Contrary Viral Strategies in Similar Disguise.

• DOI: 10.3390/microorganisms9071389
• 发表时间: 2021-06-27
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Duerr R;Crosse KM;Valero-Jimenez AM;Dittmann M
• 通讯作者: Dittmann M

Longitudinal analysis of humoral immunity against SARS-CoV-2 Spike in convalescent individuals up to 8 months post-symptom onset.

• DOI: 10.1016/j.xcrm.2021.100290
• 发表时间: 2021-06-15
• 期刊: Cell reports. Medicine
• 作者: Anand SP;Prévost J;Nayrac M;Beaudoin-Bussières G;Benlarbi M;Gasser R;Brassard N;Laumaea A;Gong SY;Bourassa C;Brunet-Ratnasingham E;Medjahed H;Gendron-Lepage G;Goyette G;Gokool L;Morrisseau C;Bégin P;Martel-Laferrière V;Tremblay C;Richard J;Bazin R;Duerr R;Kaufmann DE;Finzi A
• 通讯作者: Finzi A

A site of vulnerability at V3 crown defined by HIV-1 bNAb M4008_N1.

• DOI: 10.1038/s41467-021-26846-z
• 发表时间: 2021-11-09
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Chan KW;Luo CC;Lu H;Wu X;Kong XP
• 通讯作者: Kong XP

Cross-Sectional Evaluation of Humoral Responses against SARS-CoV-2 Spike.

• DOI: 10.1016/j.xcrm.2020.100126
• 发表时间: 2020-10-20
• 期刊: Cell reports. Medicine
• 作者: Prévost J;Gasser R;Beaudoin-Bussières G;Richard J;Duerr R;Laumaea A;Anand SP;Goyette G;Benlarbi M;Ding S;Medjahed H;Lewin A;Perreault J;Tremblay T;Gendron-Lepage G;Gauthier N;Carrier M;Marcoux D;Piché A;Lavoie M;Benoit A;Loungnarath V;Brochu G;Haddad E;Stacey HD;Miller MS;Desforges M;Talbot PJ;Maule GTG;Côté M;Therrien C;Serhir B;Bazin R;Roger M;Finzi A
• 通讯作者: Finzi A