Exploiting the antigenic conservation of the Env trimer apex across primate lentiviral lineages for AIDS vaccine design

利用跨灵长类慢病毒谱系的 Env 三聚体顶端的抗原保守性进行艾滋病疫苗设计

基本信息

批准号：
10426107
负责人：
Beatrice H Hahn
金额：
$ 80.23万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10426107
关键词：
AIDS Vaccines AIDS vaccine development Acquired Immunodeficiency Syndrome Affinity African Antibodies Antigens Autologous Award B-Lymphocytes Behavior Binding Biology CD4 Positive T Lymphocytes Cameroon Cell surface Cells Central Africa Cercopithecidae Collection Communities Complement Consensus Country Data Development Ecology Epitopes Funding Genetic Genome Glycoproteins Goals Gorilla gorilla Grant HIV HIV Envelope Protein gp120 HIV-1 HIV-1 vaccine Human Immunization Immunize Immunobiology Immunogenetics In Vitro Kinetics Knock-in Knock-in Mouse Knowledge Macaca mulatta Malaria Maps Mediating Messenger RNA Molecular Epidemiology Monkeys Mus Pan Genus Parasites Pathogenicity Pattern Phase Plasmodium falciparum Plasmodium vivax Pongidae Primate Lentiviruses Primates Production Protomer Public Health Publications Recording of previous events Research Risk SIV Specimen Structure T-Cell Depletion Tail Testing Time United States National Institutes of Health Vaccine Design Vertebral column Viral Pathogenesis Viral reservoir Virus Virus Diseases Virus-like particle Work Zoonoses base cross reactivity gene function gp160 immunogenicity microbiota neutralizing antibody novel novel strategies pandemic disease pathogen research clinical testing response simian human immunodeficiency virus transmission process vaccine development

项目摘要

PROJECT SUMMARY Studying Natural SIV Reservoirs and Human Zoonotic Risk, we discovered in the last funding period that certain strains of SIV infecting Old World monkeys and African apes share unexpected antigenic cross- reactivity with HIV-1 in the functionally important V1V2 region of the envelope glycoprotein (Env) trimer apex (44). This antigenic conservation renders these viruses uniquely sensitive to HIV-1 elicited V2 apex broadly neutralizing antibodies (bNabs) and suggests that SIV Envs, because of their extensive backbone diversity but highly conserved trimer apex antigenicity, could serve to “immunofocus” B cell responses in humans to this bNab epitope. Preliminary data in knock-in mice expressing the inferred unmutated common ancestor (UCA) of the V2 apex bNab CH01 (heavy chain only) provide supporting evidence: Immunization of these mice with a germline targeting SIVcpz Env SOSIP trimer (MT145.Q171K) elicited antibodies that not only neutralized viruses containing the autologous SIVcpz Env, but also viruses bearing Envs of heterologous HIV-1 strains (59). These results suggest that highly divergent SIVcpz (and other SIV) Envs can prime human V2 apex UCA B cells and induce bNab responses that cross-react with heterologous tier 2 HIV-1 strains (59). Utilizing our extensive knowledge of the evolutionary history, immunobiology and pathogenicity of the primate precursors of HIV-1 (summarized in 102 Progress Publications), we propose in this competing renewal of our MERIT award (R37 AI050529) to systematically explore the potential utility of SIVcpz and other SIV Envs as novel components of an AIDS vaccine. Our scientific premise is that the quaternary structure of the Env trimer apex is highly conserved across divergent SIV lineages because it mediates essential functions related to the biology of the unliganded Env glycoprotein, and that this structural conservation is reflected in conserved antigenicity. Our hypothesis is that evolutionarily divergent SIVcpz (and other SIV) Envs, when expressed as chimeric simian-human immunodeficiency viruses (SHIVs), mRNA-encoded cell surface expressed gp160 trimers, and/or virus-like particles (VLPs) in rhesus macaques (RMs), will elicit V2 apex bNabs that cross-react with HIV-1. To test this hypothesis, we will (i) characterize the extent of the V2 apex antigenic conservation across Envs from diverse primate lentiviral lineages and elucidate associated structure-function-antigenicity relationships relevant to vaccine design (Aim #1), (ii) define the potential of primate lentiviral Envs to elicit V2 apex bNabs in the context of SHIV infections (Aim #2), and (iii) determine if primate lentiviral Envs when delivered as mRNA/LNP or VLP immunogens can immunofocus V2 apex bNab responses in RMs, alone or in combination with heterologous SHIVs (Aim #3). Our application is timely because the SIVcpz MT145.Q171K Env SOSIP trimer has been selected by the NIH for GMP production and advancement to Phase 1 clinical testing in humans. The work we propose will provide an important complement and “guidepost” to the immunogenicity studies planned in humans, and thus inform and accelerate AIDS vaccine development.

项目摘要研究天然SIV水库和人的人畜共患风险，我们在最后一个资金期间发现某些SIV感染的旧世界猴子和非洲猿人共享意外的抗原交叉 - 在包膜糖蛋白（ENK）Trimer Apex的功能重要V1V2区域中与HIV-1的反应性（44）。这种抗原保护使这些病毒对HIV-1唯一敏感的V2顶点广泛敏感中和抗体（BNABS），并暗示SIV由于其广泛的主链多样性，但高度组成的三聚体顶点抗原性可以用于人类中的“免疫焦点” B细胞反应 BNAB情节。敲入小鼠的初步数据表达了推断的未分离的普通祖先（UCA） V2 Apex BNAB CH01（仅重链）提供支持证据：这些小鼠的免疫靶向SIVCPZ ENV SOSIP Trimer（MT145.Q171K）的生殖线引起不仅中和的抗体含有自体SiVCPZ Env的病毒，但还带有异源HIV-1菌株的EDRUSE （59）。这些结果表明，高度不同的SIVCPZ（和其他SIV）ENV可以使人类V2 Apex UCA启用 B细胞并诱导与异源2 HIV-1菌株交叉反应的BNAB反应（59）。利用我们的对进化史，免疫生物学和致病性的广泛了解 HIV-1（在102个进度出版物中总结），我们在此优点奖的竞争中提出了建议（R37 AI050529）系统地探索SIVCPZ和其他SIV ENV的潜在效用艾滋病疫苗的成分。我们的科学前提是env触发的第四纪结构顶点在不同的SIV谱系中高度保守，因为它介导了与非配体的ENV糖蛋白的生物学，并且这种结构保护反映在保守抗原性。我们的假设是，当表示为进化上的SIVCPZ（和其他SIV）所在嵌合Simian-Human免疫缺陷病毒（SHIV），mRNA编码的细胞表面表达GP160 恒河猕猴（RMS）中的三聚体和/或病毒样颗粒（VLP）将引起交叉反应的V2 Apex bnabs 与HIV-1。为了检验这一假设，我们将（i）表征V2顶点抗原保护的程度各种灵长类动物慢病毒谱系的环境以及阐明相关的结构 - 功能 - 抗原性与疫苗设计相关的关系（目标＃1），（ii）定义了灵长类动物慢病毒ENV的潜力在SHIV感染的背景下（AIM＃2）的Apex BNABS，（iii）确定灵长类动物慢病毒是否何时以mRNA/LNP或VLP免疫原的递送可以单独或在RMS中的Immunofocus V2 Apex BNAB响应，单独或在结合异源湿度（AIM＃3）。我们的应用程序及时，因为SIVCPZ MT145.Q171K NIH已选择了ENV SOSIP触发器，用于GMP的生产和前进到第1阶段人类的临床测试。我们提出的工作将为在人类中计划的免疫原性研究，从而为艾滋病疫苗的开发提供了信息和加速。

项目成果

期刊论文数量（110）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The ecology and epidemiology of malaria parasitism in wild chimpanzee reservoirs.

DOI：
10.1038/s42003-022-03962-0
发表时间：
2022-09-27
期刊：
Communications biology
影响因子：
5.9
作者：
通讯作者：

Wild chimpanzee offspring exhibit adult‐like foraging patterns around the age of weaning

野生黑猩猩后代在断奶时表现出类似成人的觅食模式

DOI：
10.1002/ajpa.24267
发表时间：
2021
期刊：
American Journal of Physical Anthropology
影响因子：
2.8
作者：
Lonsdorf, Elizabeth V.;Stanton, Margaret A.;Wellens, Kaitlin R.;Murray, Carson M.
通讯作者：
Murray, Carson M.

Ape Origins of Human Malaria.

DOI：
10.1146/annurev-micro-020518-115628
发表时间：
2020-09-08
期刊：
Annual review of microbiology
影响因子：
10.5
作者：
Sharp PM;Plenderleith LJ;Hahn BH
通讯作者：
Hahn BH

Natural cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling.

DOI：
10.1073/pnas.2023776118
发表时间：
2021-01-19
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Hayn M;Blötz A;Rodríguez A;Vidal S;Preising N;Ständker L;Wiese S;Stürzel CM;Harms M;Gross R;Jung C;Kiene M;Jacob T;Pöhlmann S;Forssmann WG;Münch J;Sparrer KMJ;Seuwen K;Hahn BH;Kirchhoff F
通讯作者：
Kirchhoff F

Identification and molecular characterization of new STLV-1 and STLV-3 strains in wild-caught nonhuman primates in Cameroon.

喀麦隆野生捕获的非人灵长类动物中新 STLV-1 和 STLV-3 毒株的鉴定和分子特征。

DOI：
10.1016/j.virol.2007.09.037
发表时间：
2008
期刊：
Virology
影响因子：
3.7
作者：
Liegeois,Florian;Lafay,Benedicte;Switzer,WilliamM;Locatelli,Sabrina;Mpoudi-Ngole,Eitel;Loul,Severin;Heneine,Walid;Delaporte,Eric;Peeters,Martine
通讯作者：
Peeters,Martine