Boosting cell-intrinsic innate immune recognition of HIV-1 by dendritic cells

增强树突状细胞对 HIV-1 的细胞内在先天免疫识别

基本信息

批准号：
9241321
负责人：
JEREMY LUBAN
金额：
$ 58.64万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241321
关键词：
Acquired Immunodeficiency Syndrome Animal Model Anti-Retroviral Agents Antigen Presentation Antigens Antiviral Response Attenuated Live Virus Vaccine Attenuated Vaccines Autologous Bypass CD8-Positive T-Lymphocytes Capsid Cell Maturation Cells Collaborations Cytotoxic T-Lymphocytes DNA Packaging Dendritic Cells Detection Development Failure Fetal Liver Generations Glycoproteins HIV-1 HIV-1 vaccine HLA-A2 Antigen Human Human Resources Immune Immune response Immune signaling Immune system Immunity Immunization Immunize Immunoglobulin G In Vitro Infection Integration Host Factors Interferons Interleukin-12 Interleukin-7 Intervention JUN gene Leukocytes Macrophage Colony-Stimulating Factor Mediating Modeling Modification Molecular Molecular Virology Mus Nucleic Acids Outcome Pathway interactions Pattern Pattern recognition receptor Peptides Proteins Protocols documentation Receptor Signaling Retroviridae Reverse Transcription SIV Signal Transduction Smallpox T-Lymphocyte TREX1 gene TRIM5 gene Testing Transcript Transgenes Vaccination Vaccine Design Vaccines Variant Vesicular stomatitis Indiana virus Viral Viral Antigens Virion Virus Walkers Work antiviral immunity base cellular engineering cellular transduction effectiveness measure experimental study humanized mouse improved improved outcome in vivo innovation knock-down monocyte neutralizing antibody nuclease pathogen prevent public health relevance response sensor tool vaccine development

项目摘要

DESCRIPTION (provided by applicant): 2.5 million people became infected with HIV-1 in 2011. Clearly, a vaccine that prevents HIV-1 infection is needed. The immune response to HIV-1, though, differs fundamentally from that of other viruses such as smallpox for which effective vaccines have been developed. In the face of documented HIV-1-specific humoral and cellular immune responses, HIV-1-infected people progress to AIDS and can even be secondarily infected with HIV-1. Without critical modifications to vaccine design based on understanding of anti-HIV-1 immunity, even a live-vaccine would not prevent HIV-1 infection. Anamnestic, antiviral responses, including cytotoxic T lymphocytes and neutralizing antibodies, require priming of naïve, antigen-specific T cells by DCs that have matured sufficiently to produce an array of signals and factors, including IL-12. Such maturation is optimal for priming antiviral responses when pattern recognition receptors (PRRs) are activated within the same DCs that present viral antigen (intrinsic detection). The dominant pathway by which HIV-1 enters conventional, antigen-presenting DCs permits efficient HIV-1 antigen presentation but precludes maturation: reverse transcription does not occur, PRRs are not activated, and type 1 interferon is not produced. T cell priming in the absence of DC maturation provides an explanation for well-described, ineffective anti-HIV-1 immune responses. To maximize DC maturation and improve the outcome of HIV-1-specific T cell priming, the experiments proposed here will increase intrinsic recognition of HIV-1 by PRRs within the same DCs that present HIV-1 antigen. This will be done by redirecting HIV-1 to a productive DC-entry pathway by pseudo-typing with VSV Glycoprotein and exploiting recent discoveries concerning innate immune sensing of HIV-1 within DCs: TRIM5-mediated NF-κB and c-Jun signaling will be activated in DCs by engineered modifications in the HIV-1 capsid; nascent HIV-1 reverse transcription in DCs will be permitted by blocking the triphosphohydrolase SAMHD1; disruption of DC nucleases TREX1 and RNASEH2 will permit HIV-1 reverse transcripts to accumulate to levels that activate type 1 IFN; PRRs such as cGAS will be delivered by HIV-1 itself in order to amplify innate immune signaling. The combination of these interventions that matures DCs to optimally prime anti-HIV-1-specific CD4+ and CD8+ T cell responses will be identified and these conditions will be used to immunize state-of-the-art, humanized mice, in which we have already detected HIV-1 strain-specific neutralizing antibodies. These experiments will determine if intrinsic sensing of HIV-1 by DCs improves acquired immune responses to HIV-1 and, if it does, offer a roadmap for the development of potent, anti-HIV-1 vaccines in people.

描述（由申请人提供）：2011 年有 250 万人感染了 HIV-1。显然，需要一种预防 HIV-1 感染的疫苗。不过，对 HIV-1 的免疫反应与其他病毒（例如病毒）的免疫反应有根本不同。面对已记录的 HIV-1 特异性体液和细胞免疫反应，HIV-1 感染者会发展为艾滋病，甚至可能继发感染 HIV-1。如果不基于对抗 HIV-1 免疫的了解对疫苗设计进行重大修改，即使是活疫苗也无法预防 HIV-1 感染。记忆性抗病毒反应（包括细胞毒性 T 淋巴细胞和中和抗体）需要启动初始抗原。 DC 已充分成熟以产生一系列信号和因子（包括 IL-12），这种成熟对于在同一 T 细胞内激活模式识别受体 (PRR) 时引发抗病毒反应是最佳的。呈递病毒抗原的 DC（内在检测）。HIV-1 进入常规抗原呈递 DC 的主要途径允许 HIV-1 抗原呈递，但阻止成熟：不会发生反向有效转录，PRR 不会被激活，并且 1 型。在 DC 不成熟的情况下，T 细胞不会产生干扰素，这为充分描述的无效抗 HIV-1 免疫反应提供了解释，以最大限度地提高 DC 成熟并改善 HIV-1 特异性 T 的结果。细胞启动，这里提出的实验将增加呈递 HIV-1 抗原的相同 DC 内的 PRR 对 HIV-1 的内在识别，这将通过用 VSV 进行假分型将 HIV-1 重定向到有效的 DC 进入途径来完成。糖蛋白和利用有关 DC 内 HIV-1 先天免疫感应的最新发现：TRIM5 介导的 NF-κB 和 c-Jun 信号传导将通过 HIV-1 衣壳的工程修饰在 DC 中激活；通过阻断三磷酸水解酶 SAMHD1，DC 中新生的 HIV-1 逆转录将被允许；破坏 DC 核酸酶 TREX1 和 RNASEH2 将允许 HIV-1 逆转录积累到激活 1 型 IFN 的水平，例如 HIV 传递的 cGAS； -1 本身，以放大先天免疫信号传导，这些干预措施的组合使 DC 成熟，以最佳地启动抗 HIV-1 特异性 CD4+ 和 CD8+。 T 细胞反应将被鉴定，这些条件将用于免疫最先进的人源化小鼠，在这些小鼠中我们已经检测到了 HIV-1 毒株特异性中和抗体。 DC 的 1 改善了对 HIV-1 的获得性免疫反应，如果确实如此，将为人类开发有效的抗 HIV-1 疫苗提供路线图。