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Prevention of HIV-induced T cell killing by autophagy

通过自噬预防 HIV 诱导的 T 细胞杀伤

基本信息

批准号：
9761444
负责人：
Michael Aaron Mandell
金额：
$ 18.94万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
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：
2018-08-10 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761444
关键词：
AIDS prevention Acquired Immunodeficiency Syndrome Anti-inflammatory Antiinflammatory Effect Antiviral Agents Autophagocytosis Blood CASP1 gene CD4 Positive T Lymphocytes Capsid Cell Culture Techniques Cell Death Cell Line Cell model Cells Cessation of life Chronic Clinical Comorbidity Complex Coronary Detection Disease Ensure Excision HIV HIV Infections HIV-1 Human Immune In Vitro Infection Inflammation Inflammatory Inflammatory Response Integration Host Factors Interleukin-1 beta Ions Lead Link Lymph Lymphoid Cell Lymphoid Tissue Mediating Modeling Molecular Monitor Nature Nerve Degeneration Numbness Outcome Study Output Partner in relationship Pathogenesis Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Physiological Positioning Attribute Premature aging syndrome Process Production Property Publishing Reporting Research Rest Risk Role Signal Transduction T-Cell Depletion T-Lymphocyte Testing Tissues United States National Institutes of Health Viral Virus Virus Diseases Virus Replication Waste Management Work antiretroviral therapy cell killing cytokine experience improved in vivo inhibition of autophagy knock-down novel novel strategies pathogen premature prevent receptor response restin

项目摘要

SUMMARY HIV pathogenesis is mediated by non-protective inflammatory responses to viral infection. This is true of the primary manifestation of HIV infection that leads to AIDS, CD4+ T cell depletion, and also of certain co- morbidities such as premature aging or neurodegeneration that remain challenges for HIV patients in spite of viral suppression by antiretroviral therapy. As such, in addition to limiting viral replication, there is also a need to suppress the inflammatory cascade triggered by viral infection. The purpose of this application is to test whether autophagy, a cellular waste management pathway, could be engaged to counteract HIV-induced inflammation. Autophagy has the potential to protect against HIV pathogenesis in two ways. First, autophagy is reported to have direct antiviral activities against several viruses, including HIV. Second, autophagy can protect against inflammatory processes through multiple complimentary mechanisms. Our hypothesis is that autophagy, when “turned on” by existing drugs, can act as an anti-HIV effector mechanism and also prevent HIV-induced CD4+ T cell depletion through its anti-inflammatory activities. The understanding of inflammation’s role in HIV pathogenesis has emerged recently as a result of improved models of HIV infection. Whereas most HIV infection and inflammation takes place in lymphoid tissue in vivo, most cell culture models of HIV infection use cell lines or isolated blood-derived immune cells. While these models have been useful in many respects, they are not representative of what happens in the complex setting of lymphoid tissue. Thus, we will use a previously published ex vivo model of lymphoid tissue that will allow us to monitor the effect of autophagy induction on HIV infection and spread as well as the inflammatory depletion of CD4+ T cells under physiologically relevant conditions. We will also determine if viral or host factors implicated in initiating or transducing inflammatory responses to HIV are targets of selective autophagy as this would be one mechanism whereby autophagy could exert is anti-inflammatory effects. Completion of these aims will: i) determine if the reported anti-HIV actions of autophagy are active in a physiologically relevant model of infection, and ii) assess whether autophagy’s anti-inflammatory properties can counteract HIV-induced inflammation and T cell depletion. This work may lead to approaches to enable or enhance autophagy in ways that would mitigate HIV pathogenesis in a clinical setting. Our expertise in autophagy and in HIV will ensure a successful outcome of these studies.

总结