Tyrosine Kinase inhibition: The New Front in HIV Cure Efforts

酪氨酸激酶抑制：艾滋病毒治疗工作的新前沿

• 批准号: 10517500
• 负责人: Mayte Coiras
• 金额: $ 44.27万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-07 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10517500
• 关键词: ABL1 gene; Affect; Antiviral Response; Awareness; Biological; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Central Nervous System; Chronic Myeloid Leukemia; Clinical Trials; Cytomegalovirus; Dasatinib; Development; FCGR3B gene; FDA approved; Frequencies; Future; Goals; Granzyme; HIV; HIV Infections; HIV-1; Human; Human Herpesvirus 4; IL7 gene; Immune; Immune response; Impairment; In Vitro; Infection; Influenza; Interferons; Interleukin-15; Laboratories; Large granular lymphocyte; Macrophage; Maintenance; Malignant Neoplasms; Mediating; Microglia; Modeling; Myelogenous; Myeloid Cells; NCAM1 gene; Natural Killer Cells; Neurologic; Pathogenesis; Pathway interactions; Patients; Penetration; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Philadelphia Chromosome; Phosphorylation; Population; Production; Proliferating; Protein Dephosphorylation; Protein Tyrosine Kinase; Proto-Oncogene Protein c-kit; Public Health; Research; Signal Pathway; Signal Transduction; Stimulation of Cell Proliferation; System; T memory cell; T-Cell Proliferation; T-Lymphocyte; Testing; Threonine; Time; Tissues; Tyrosine Kinase Inhibitor; Viral; Viral Physiology; Virus Diseases; antiretroviral therapy; cell type; clinical application; cytokine; cytotoxic; fighting; frontier; immunoregulation; in vitro Model; leukemia; nonhuman primate; novel; novel therapeutics; pre-clinical; prevent; response; synergism

PROJECT ABSTRACT The major obstacle for HIV-1 eradication is the existence of a small but long-lived latent reservoir that is impervious to antiretroviral therapy. This reservoir persists largely through the natural ability of memory T cells to homeostatically proliferate in response to γc-cytokines IL-7 and IL-15. In addition, HIV-1 also infects cells of the myeloid lineage, such as macrophages, a cell type that can penetrate protected tissues including the central nervous system, and precipitate a spectrum of neurological impairments that can persist in the setting of antiretroviral therapy. Recently, several studies have demonstrated that dasatinib, a tyrosine kinase inhibitor that is FDA-approved for the treatment of chronic myeloid leukemia, has three novel activities that can specifically impact HIV-1 infection and the persistence of latent reservoirs. The first novel activity of dasatinib is the ability to block homeostatic proliferation. Thus, in Aim 1 we test the hypothesis that dasatinib will block the homeostatic proliferation of latently infected T cells and thus prevent maintenance of the latent reservoir, resulting in a faster decay over time. We also propose to identify the tyrosine kinase(s) whose inhibition by dasatinib blocks homeostatic proliferation and hypothesize that such target(s) is different from the cognate targets of dasatinib (Src, c-Abl and c-Kit). A second activity of dasatinib is its ability to block infection by HIV-1 by an unusual mechanism that involves dephosphorylation and activation of SAMHD1, a potent viral restriction factor, both in T-cells and macrophages. The signaling pathway leading to dephosphorylation of SAMHD1 at threonine-592 downstream of dasatinib is unknown, but is clearly different from that downstream of IFN signalling. Because of the high potency of the inhibitory effect in both T-cells and myeloid cells, the dasatinib-inhibited pathway represents a compelling target for discovery (the focus of Aim 2) and development of novel therapeutics. A third activity of dasatinib with relevance to viral infection lies in its potent immunomodulatory activities. Dasatinib, extensively administered and studied to CML patients, induces an expansion of large granular lymphocytes (LGLs) with cytotoxic or NK phenotype, an increase in cytotoxic populations granzyme B+, as well as a potent immune response resembling natural responses against CMV. All these effects appear to contribute to the highly effective anti-leukemic effects of dasatinib. Thus, the third Aim of these studies will be to test the hypothesis that dasatininb will enhance innate cellular immune mechanisms against HIV-infected cells. In summary, we propose to investigate these novel and promising antiviral activities of dasatinib in the context of HIV-1 infection, with a focus on understanding the biological mechanisms and evaluating the potential for future clinical application. Dasatinib therefore represents a novel front in our fight to eradicate HIV-1.

项目摘要 根除HIV-1的主要障碍是存在一个小但寿命长的潜伏储存库， 抗逆转录病毒治疗无效这种储存库主要通过记忆T细胞的自然能力而持续存在 响应γ c-细胞因子IL-7和IL-15而稳态增殖。此外，HIV-1还感染了 骨髓谱系，如巨噬细胞，一种可以穿透受保护组织的细胞类型， 神经系统，并沉淀一系列的神经功能障碍，可以持续在设置 抗逆转录病毒疗法最近，几项研究表明，达沙替尼，一种酪氨酸激酶抑制剂， FDA批准用于治疗慢性髓性白血病，有三种新的活性， 影响HIV-1感染和潜伏宿主的持续存在。 达沙替尼的第一个新活性是阻断稳态增殖的能力。因此，在目标1中，我们测试 假设达沙替尼将阻断潜伏感染的T细胞的稳态增殖， 保持潜在的水库，导致随着时间的推移更快的衰减。我们还建议确定酪氨酸 激酶，其被达沙替尼抑制阻断稳态增殖，并假设这样的靶点是 与达沙替尼的同源靶标（Src、c-Abl和c-Kit）不同。 达沙替尼的第二个活性是其通过一种不寻常的机制阻断HIV-1感染的能力， 涉及SAMHD 1的去磷酸化和激活，SAMHD 1是一种有效的病毒限制因子，在T细胞和 巨噬细胞导致SAMHD 1在苏氨酸-592下游去磷酸化的信号通路 达沙替尼的下游是未知的，但明显不同于IFN信号传导的下游。由于高 由于达沙替尼在T细胞和髓系细胞中的抑制作用的效力，达沙替尼抑制途径代表了一种 令人信服的发现目标（目标2的焦点）和新疗法的开发。 达沙替尼与病毒感染相关的第三种活性在于其有效的免疫调节活性。 达沙替尼，广泛给予和研究CML患者，诱导大颗粒的扩张， 具有细胞毒性或NK表型的淋巴细胞（LGL），细胞毒性群体颗粒酶B+增加，以及 作为一种有效的免疫反应，类似于对CMV的自然反应。所有这些影响似乎都有助于 达沙替尼的高效抗白血病作用。因此，这些研究的第三个目的将是测试 假设dasatininb将增强针对HIV感染细胞的先天细胞免疫机制。 总之，我们建议研究这些新的和有前途的抗病毒活性的达沙替尼在 HIV-1感染的背景下，重点是了解生物学机制和评估潜在的 用于未来的临床应用。因此，达沙替尼代表了我们根除HIV-1斗争的新战线。

项目成果

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation.

• DOI: 10.1016/j.bcp.2021.114844
• 发表时间: 2022-01
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Larragoite ET;Nell RA;Martins LJ;Barrows LR;Planelles V;Spivak AM
• 通讯作者: Spivak AM

Impaired Antibody-Dependent Cellular Cytotoxicity in a Spanish Cohort of Patients With COVID-19 Admitted to the ICU.

• DOI: 10.3389/fimmu.2021.742631
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Vigón L;García-Pérez J;Rodríguez-Mora S;Torres M;Mateos E;Castillo de la Osa M;Cervero M;Malo De Molina R;Navarro C;Murciano-Antón MA;García-Gutiérrez V;Planelles V;Alcamí J;Pérez-Olmeda M;Coiras M;López-Huertas MR
• 通讯作者: López-Huertas MR

Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.

• DOI: 10.1016/j.bcp.2021.114816
• 发表时间: 2021-12
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Innis EA;Levinger C;Szaniawski MA;Williams ESCP;Alcamí J;Bosque A;Schiffer JT;Coiras M;Spivak AM;Planelles V
• 通讯作者: Planelles V

HIV-1-induced type I IFNs promote viral latency in macrophages.

HIV-1诱导的I型IFN促进了巨噬细胞中的病毒潜伏期。

• DOI: 10.1002/jlb.4ma0422-616r
• 发表时间: 2022-11
• 期刊: JOURNAL OF LEUKOCYTE BIOLOGY
• 影响因子: 5.5
• 作者: Dickey, Laura L.;Martins, Laura J.;Planelles, Vicente;Hanley, Timothy M.
• 通讯作者: Hanley, Timothy M.

Identification of Immunological Parameters as Predictive Biomarkers of Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission.

• DOI: 10.3390/jcm10010042
• 发表时间: 2020-12-25
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Vigón L;Luna A;Galán M;Rodríguez-Mora S;Fuertes D;Mateos E;Piris-Villaespesa M;Bautista G;San José E;Rivera-Torres J;Steegmann JL;de Ory F;Pérez-Olmeda M;Alcamí J;Planelles V;López-Huertas MR;García-Gutiérrez V;Coiras M
• 通讯作者: Coiras M