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：
8705952
负责人：
JEREMY LUBAN
金额：
$ 60.24万
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8705952
关键词：
Acquired Immunodeficiency Syndrome Animal Model Antigen Presentation Antigens Antiviral Agents Antiviral Response Attenuated Live Virus Vaccine Attenuated Vaccines Autologous Bypass CD8B1 gene Capsid Cell Maturation Cells Collaborations Cytotoxic T-Lymphocytes DNA Packaging Dendritic Cells Detection Development Failure Fetal Liver Generations Glycoproteins HIV-1 HLA-A2 Antigen Human Human Resources Immune Immune response Immune system Immunity Immunization Immunoglobulin G In Vitro Infection Integration Host Factors Interferons Interleukin-12 Interleukin-7 Intervention JUN gene Leukocytes Life 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 cell response T-Lymphocyte TREX1 gene Testing Transcript Transgenes Vaccination Vaccine Design Vaccines Variant Vesicular stomatitis Indiana virus Viral Viral Antigens Virion Virus Walkers Work base cellular engineering effectiveness measure improved in vivo innovation knock-down monocyte neutralizing antibody nuclease pathogen prevent public health relevance research study 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 na¿ve, 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-?B 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（由适用提供）：2011年有250万人感染了HIV-1。显然，一种防止HIV-1感染的疫苗。然而，对HIV-1的免疫激发与已开发有效疫苗的其他病毒（例如天花）不同。面对有记录的HIV-1特异性体液和细胞免疫调查，HIV-1感染的人会发展为艾滋病，甚至可以被HIV-1感染。如果没有基于对抗HIV-1免疫学的理解的疫苗设计的批判性修改，即使是活疫苗也不能阻止HIV-1感染。食用的，抗病毒反应，包括细胞毒性T淋巴细胞和中和抗体，需要通过DC启动Na¿ve，抗原特异性T细胞，DC已经足够成熟，以产生一系列信号和因素，包括IL-12。当在呈现病毒抗原的相同DC中激活模式识别受体（PRR）时，这种成熟对于启动抗病毒反应是最佳的（固有检测）。 HIV-1进入常规的，抗原呈递DCS的主要途径允许有效的HIV-1抗原呈递但排除成熟：不发生逆转录，未激活PRR，并且未产生1型1层干扰素。在没有直流成熟的情况下，T细胞启动提供了一种解释，解释了良好的，无效的抗HIV-1免疫调查。为了最大化直流成熟并改善HIV-1特异性T细胞启动的结果，此处提出的实验将增加PRR对HIV-1对HIV-1抗原的内在识别。这将通过将HIV-1重定向到富有生产力的DC进入途径来实现，通过使用VSV糖蛋白进行伪型，并利用有关DCS中HIV-1的先天免疫传感的最新发现：TRIM5介导的NF-？B？b？b？b？j jun信号和C-Jun信号在DC中通过工程学的Modivications在DC中被激活。 DC中的新生HIV-1逆转录将通过阻断三磷酶SAMHD1来允许。 DC核的破坏TREX1和RNASEH2将允许HIV-1逆转录本累积到激活1型IFN的水平； HIV-1本身将提供诸如CGA之类的PRR，以扩大先天免疫信号。这些干预措施的结合将确定为最佳抗HIV-HIV-1特异性CD4+和CD8+ T细胞反应，并将确定这些条件，这些条件将用于免疫最先进的人性化小鼠，在该小鼠中我们已经检测到HIV-1菌株特异性中和中和中和中和抗体。这些实验将确定HIV-1是否通过 DCS改善了对HIV-1的免疫回报，如果确实如此，则为人们提供了潜在的抗HIV-1疫苗的路线图。