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Understand the role of CARD8 inflammasome in HIV-1 infection

了解 CARD8 炎性体在 HIV-1 感染中的作用

基本信息

批准号：
10327114
负责人：
LIANG SHAN
金额：
$ 70.2万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-21 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10327114
关键词：
Adaptive Immune System Amino Acid Sequence Antibodies Apoptotic Binding Biological Assay Blood C-terminal CASP1 gene CD28 gene CD3 Antigens CD4 Positive T Lymphocytes Cell Death Cell Line Cells Chemicals Cleaved cell Combined Modality Therapy Complex DNA Dimerization Early treatment Epitopes Evaluation Frequencies Gene Expression Genome Grant HIV HIV Protease HIV-1 HIV-1 protease Human Immune Immune system In Vitro Individual Infection Inflammasome Inflammation Interleukin-1 beta Interruption Investigation Knock-in Mouse Libraries Ligands Measures Mediating Molecular Molecular Conformation Mus Mutation N-terminal NNRTI-resistance Names Patients Pattern recognition receptor Peptide Hydrolases Pharmaceutical Preparations Physiological Plasma Protein Precursors Proteins RNA Regimen Reporter Research Resistance Rest Role Shock Signal Transduction T-Lymphocyte Testing Time Tissues Variant Viral Viral Cytopathogenic Effect Viral Genes Viral Proteins Viral reservoir Virus Virus Activation Virus Latency antiretroviral therapy base clinical subtypes cytokine efavirenz high throughput screening humanized mouse immune clearance in vivo latent HIV reservoir macrophage memory CD4 T lymphocyte microbial mouse model non-nucleoside reverse transcriptase inhibitors novel strategies pol Gene Products premature prevent protein function resistance mutation response screening viral RNA viral rebound

项目摘要

Abstract Despite antiretroviral therapy (ART), HIV-1 infection is not curable due to the presence of viral latent reservoirs primarily in long-lived resting memory CD4+ T cells. The viral latent reservoirs are the major barrier to HIV-1 eradication. The “shock and kill” strategy for HIV-1 eradication involves the use of latency-reversing agents (LRAs) to induce viral gene expression, which renders the infected cells susceptible to viral cytopathic effects or immune clearance. However, in ART-treated patients, the latent HIV-1 resides in cells is resistant to viral- or immune-mediated apoptotic cell death and often carries mutations to escape recognition by T cells or antibodies. Therefore, novel approaches to target immutable components of the virus such as essential viral protein functions are needed. Inflammasome is a critical molecular complex that mediates inflammation and pyroptotic cell death in response to microbial or danger signals. In humans, the physiologic ligand(s) for the CARD8 inflammasome remains unknown. Our studies demonstrate that HIV-1 protease degrades the CARD8 N-terminal domain and releases the C-terminus for inflammasome activation. In HIV-1-infected cells, the viral protease remains inactive as a subunit of viral Gag-Pol polyprotein. After virus budding, it is activated through Gag-Pol dimerization. We show that premature activation of intracellular HIV-1 protease by non-nucleoside reverse transcriptase inhibitors (NNRTI) triggers CARD8 sensing and killing of HIV-infected macrophages and CD4+ T cells. All subtypes of HIV-1 can be sensed by CARD8 despite substantial viral diversity. Our finding suggests that targeted activation of CARD8 inflammasome is a promising strategy to eliminate latent HIV-1 reservoirs. In this proposed study, we will: 1) perform ex vivo assessment and optimization of the CARD8-based “shock and kill strategy” for clearing latent HIV-1 in patient CD4+ T cells; 2) understand the molecular mechanisms of HIV-1 protease- mediated CARD8 inflammasome activation; 3) test CARD8-based “shock and kill” strategy in humanized mouse model of HIV-1 latency. Our proposed study will advance the understanding of the physiological mechanisms of CARD8 inflammasome activation and its role in HIV-1 infection, which will provide critical implications to HIV cure research.

摘要