A radiation-induced cellular stress activates HIV and induces killing of infected cells

辐射引起的细胞应激会激活艾滋病毒并诱导杀死受感染的细胞

• 批准号: 9326140
• 负责人: Fatah Kashanchi
• 金额: $ 22.8万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326140
• 关键词: Agonist; Anti-Retroviral Agents; Apoptosis; Autophagocytosis; Binding; CASP1 gene; CD4 Positive T Lymphocytes; Calpain; Cell Cycle; Cell Death; Cell Line; Cell Survival; Cells; Cellular Stress; Cessation of life; Chronic; Cultured Cells; Cyclins; DNA Damage; DNA Polymerase II; Data; Dose; Epigenetic Process; Genetic Transcription; Genome; Goals; HDAC1 gene; HIV; HIV-1; Highly Active Antiretroviral Therapy; Human; Human immunodeficiency virus test; Immune response; Immune system; Individual; Induction of Apoptosis; Interleukin-7; Methods; Mus; Nuclear; Organ; Outcome; Patients; Pharmaceutical Preparations; Phosphorylation; Plasma; Population; Positive Transcriptional Elongation Factor B; Production; Proteasome Inhibitor; Publishing; RNA; RNA Polymerase II; Radiation; Rest; Reverse Transcriptase Polymerase Chain Reaction; Roentgen Rays; S Phase; Scheme; Shock; Signal Transduction; Specificity; Stress; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Tissues; Transcriptional Activation; Transferase; Viral; Viral Proteins; Viral reservoir; Virus; Virus Replication; Western Blotting; bryostatin; cancer therapy; chromatin immunoprecipitation; cytotoxic; humanized mouse; in vivo; inhibitor/antagonist; irradiation; killings; macrophage; promoter; repaired; response; transcription factor; viral RNA

HIV-1 can be preserved in the long-lived resting CD4+ T cells which form a viral reservoir in infected individuals. This reservoir may persist for many years even though the patients are usually treated with highly active antiretroviral therapy (HAART), and viral population can be recovered once HAART is stopped. Thus, the selective activation of the latently HIV-infected cells resulting in the replication of proviral genome is critical to make infected cells recognized by immune system. Our long term goal is to find the method of reactivation of HIV from latency and killing of infected cells that does not kill or destroy non-infected quiescent cells and subsequently target and eradicate the persistent HIV-1 reservoirs. We have preliminary data showing that a well-characterized stress signal, such as irradiation (IR), activated inappropriate entry of the HIV infected T cells to S phase of the cell cycle and increased viral transcription and eventual apoptosis of infected cells. Importantly, the parental uninfected cells did not demonstrate this response to the same irradiation dose. Our recently published data elucidated this phenomenon and indicated (1) increase of HIV-1 transcription via epigenetic mechanisms after the IR-induced DNA damage, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter; (2) elevated level of intracellular HIV-1 RNA and increased expression of viral proteins in the IR-treated HIV-1 infected quiescent CD4+ T cells; (3) enhancement of transcription activation in latently HIV-1infected macrophages treated with PKC agonist bryostatin 1 after IR; (4) higher death of irradiated HIV-1 chronically-infected cells via increased phosphorylation of Ser46 in p53 that is responsible for apoptosis induction. Finally, (5) exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma and certain tissue viral reservoirs. We hypothesize, that the cellular stress induced by low IR doses reactivates HIV-1 transcription from latently infected cells resulting in nuclear accumulation of Tat, activation of HIV-1 genome expression and enhanced apoptosis of infected, but not uninfected, cells. Our two aims include; A) To identify the mechanism of HIV-1 reactivation in response to therapeutic X-ray doses in latently infected T cells and to assess IR effect on the Tat activated HIV-1 transcription; and B) To decipher mechanism of enhanced apoptosis of HIV-1 infected cells in response to IR doses. The expected outcomes of these proposed studies include elucidation of the mechanisms that determine HIV-1 reactivation and apoptosis in latently infected cells and tissues in response to the X ray IR. We also expect to determine optimal IR dose that does not destroy uninfected cells, but induces HIV-1 reactivation and apoptosis of latently infected cells.

HIV-1可以保存在长期休眠的CD4+ T细胞中，这些细胞在被感染的细胞中形成病毒库