Therapeutic Dendritic Cell Vaccine for HIV

HIV 治疗性树突状细胞疫苗

基本信息

批准号：
10343711
负责人：
Nathaniel R. Landau
金额：
$ 84.75万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343711
关键词：
Acquired Immunodeficiency Syndrome Anti-Retroviral Agents Antigens Antiviral Therapy Autologous Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Chimeric Proteins Clinical Cytotoxic T-Lymphocytes Dendritic Cell Vaccine Dendritic Cells Detection Engineering Epitopes Frequencies Genes HIV HIV Genome HIV vaccine HIV-1 Histocompatibility Immune checkpoint inhibitor Immune response Immunity Individual Lentivirus Vector Lymphocytic choriomeningitis virus Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Proteins Regimen Resistance SIV Specificity T cell response T-Lymphocyte Testing Therapeutic Time Vaccines Viral Viral Proteins Viral Vector Viral load measurement Virion Virus Virus Replication antigen-specific T cells antiretroviral therapy cellular transduction cytokine enzyme linked immunospot assay exhaust exhaustion humanized mouse in vitro testing in vivo mouse model prevent receptor response therapeutic vaccine vector

项目摘要

Project Summary The presence of a long-lived reservoir of latently infected CD4 T cells in HIV infected individuals requires that they remain on antiretroviral drug regimens life-long. Rare elite controllers maintain virus loads below the level of detection by standard clinical assays without antiretroviral treatment. The ability of such individuals to suppress virus replication is associated with antiviral cytolytic T cells that are resistant to exhaustion as a result of continuous receptor stimulation and checkpoint activation. The project will develop a therapeutic lentiviral vector-based dendritic cell (DC) vaccine that enhances CD8 T cell responses and reverses exhaustion to achieve a functional cure in which virus replication is suppressed without antiviral therapy. The vaccine is based on lentiviral vectors delivered in virions that contain the SIV accessory protein Vpx for high efficiency DC transduction and that express HIV-1 antigen, an immunostimulatory cytokine and a checkpoint inhibitor. The antigen will be expressed as a fusion protein that allows for TAP-independent presentation on class I major histocompatibility proteins. The ability of the vectors to induce anti-viral T cell responses will be tested in vitro and in vivo. AIDS patient peripheral blood mononuclear cell-derived DCs will be transduced with the vectors and tested for their ability to activate and expand autologous HIV-specific T cells in a high throughput ELISPOT assay that determines the epitope specificity and frequency of responding CD8 T cells across the HIV genome. The ability of vector-transduced DCs to induce antigen specific T cells and to suppress virus load will be determined in a humanized mouse model. The ability of the vaccine to reverse T cell exhaustion and to stimulate protective responses will be evaluated in the lymphocytic choriomeningitis virus mouse model. In addition, Vpx-containing lentiviral vectors will be tested in an engineered immunity approach for the long-term in vivo expression of antiviral proteins in DCs.

项目摘要在艾滋病毒感染的个体中，存在长期感染的CD4 T细胞的长寿命储层要求他们保留在抗逆转录病毒药物方面生命。稀有精英控制器将病毒负荷保持在水平以下通过标准临床测定未经抗逆转录病毒治疗的检测。这样的人的能力抑制病毒复制与抗病毒细胞溶解T细胞相关连续受体刺激和检查点激活的结果。该项目将开发一种治疗性基于慢病毒载体的树突状细胞（DC）疫苗，可增强CD8 T细胞反应和逆转疲惫以实现功能固化，在没有抗病毒治疗的情况下抑制病毒复制。这疫苗基于在含有SIV辅助蛋白VPX的病毒体中传递的慢病毒载体。效率直流转导和表达HIV-1抗原，免疫刺激性细胞因子和检查点抑制剂。抗原将表示为融合蛋白，可在 I类主要的组织相容性蛋白。向量诱导抗病毒T细胞反应的能力将是在体外和体内测试。 AIDS患者外周血单核细胞衍生的DC将被转导使用矢量并测试了它们激活和扩展自体HIV特异性T细胞的能力确定响应CD8 T细胞的表位特异性和频率的吞吐量ELISPOT测定跨越HIV基因组。载体转导DC诱导抗原特异性T细胞的能力和抑制病毒负荷将在人源化小鼠模型中确定。疫苗反向T的能力细胞衰竭和刺激保护性反应将在淋巴细胞脉络膜脑膜炎中评估病毒小鼠模型。此外，将在工程免疫力中测试含VPX的慢病毒载体 DC中抗病毒蛋白长期体内表达的方法。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SARS-CoV-2 Infects Syncytiotrophoblast and Activates Inflammatory Responses in the Placenta.

DOI：
10.1101/2021.06.01.446676
发表时间：
2021-06-17
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Argueta, Lissenya B;Lacko, Lauretta A;Stuhlmann, Heidi
通讯作者：
Stuhlmann, Heidi

Convalescent-Phase Sera and Vaccine-Elicited Antibodies Largely Maintain Neutralizing Titer against Global SARS-CoV-2 Variant Spikes.

DOI：
10.1128/mbio.00696-21
发表时间：
2021-06-29
期刊：
mBio
影响因子：
6.4
作者：
Tada T;Dcosta BM;Samanovic MI;Herati RS;Cornelius A;Zhou H;Vaill A;Kazmierski W;Mulligan MJ;Landau NR
通讯作者：
Landau NR

The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target.

DOI：
10.1038/s41418-021-00900-1
发表时间：
2022-03
期刊：
Cell death and differentiation
影响因子：
12.4
作者：
Rona G;Zeke A;Miwatani-Minter B;de Vries M;Kaur R;Schinlever A;Garcia SF;Goldberg HV;Wang H;Hinds TR;Bailly F;Zheng N;Cotelle P;Desmaële D;Landau NR;Dittmann M;Pagano M
通讯作者：
Pagano M

Partial resistance of SARS-CoV-2 Delta variants to vaccine-elicited antibodies and convalescent sera.