The adenosine system in viral reservoir persistence

病毒储存库持久性中的腺苷系统

• 批准号: 8544675
• 负责人: JAY RAPPAPORT
• 金额: $ 58.05万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544675
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Address; Adenosine; Adenosine Triphosphate; Animals; Anti-Retroviral Agents; Antiviral Agents; Autologous; Biological Markers; Biological Neural Networks; Brain; CD4 Positive T Lymphocytes; Cell Count; Cell Death; Cells; Cognition Disorders; Cognitive; Data; Dendritic Cells; Development; Disease; Encephalitis; Endothelial Cells; Enzymes; Exhibits; HIV; HIV Infections; HIV encephalitis; Immune; Immune response; Impairment; In Vitro; Infection; Life; Ligands; Location; Longitudinal Studies; Macaca mulatta; Measures; Mediating; Metabolism; Microglia; Minor; Modeling; Motor; Mus; Nature; Neurocognitive; Neurocognitive Deficit; Neurologic; Nodule; Pathogenesis; Patients; Penetrance; Performance; Phenotype; Plasma; Play; Production; Purinergic P1 Receptors; Regulatory T-Lymphocyte; Relative (related person); Reporting; Resistance; Role; SIV; SIV encephalitis; Synaptic Transmission; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Viral; Viral Load result; Viremia; Virus; antiretroviral therapy; brain tissue; cytokine; design; extracellular; immunoregulation; in vivo; macrophage; monocyte; nervous system disorder; novel; novel therapeutic intervention; pathogen; public health relevance; receptor; regenerative; relating to nervous system; response; therapy design

DESCRIPTION (provided by applicant): HIV infection of the CNS persists despite antiretroviral treatment, representing a challenge for treatment of neurologic disorders and a significant hurdle for the eradication of HIV in treated patients. It is likely that elimination ofHIV infected reservoirs in the brain will require interventions designed to stimulate immune recognition of HIV infected cells and/or circumvent immune suppressive mechanisms. Adenosine triphosphate (ATP) is a potent immune stimulant, acting via P2-type receptors on immune cells. Adenosine, in contrast, has potent immune suppressive activities on T cells and macrophages/dendritic cells via P1-type receptors. Microglia in CNS, similar to an action of regulatory T cells, express ectonucleotidases CD39 and CD73, which convert ATP and ADP to AMP (via CD39), with further metabolism to adenosine (via CD73), providing a potentially important mechanism mediating immune modulation. In our preliminary studies in CNS tissues from SIV infected rhesus macaques, both CD39 and CD73 exhibit increased expression relative to uninfected control brain tissue. The expression of both ectoenzymes is markedly increased on parenchymal microglia in SIV infected brain, even in the absence of encephalitis. In addition, CNS perivascular macrophages and cells within microglial nodules, highly express these enzymes in the setting of SIV encephalitis In our proposed studies, we will test the hypothesis that ATP metabolism, via the enzymatic activities of CD39 and CD73 expression on microglia, is increased in the CNS in SIV infected rhesus macaques, contributes to the survival of infected cells, and impairs virus specific immune responses. In Specific Aim I, we will test the hypothesis that CD39 and CD73 expression on microglia, is increased in SIV infection and determine the impact of cART treatment on expression and enzymatic activity. We will further evaluate ATP metabolites as biomarkers in CSF during the course of this study and determine if values correlate with SIV infection status, biologic and virologic markers for pathogenesis, CD39 and CD73 expression in CNS, and the response to cART treatment. We will test the hypothesis increased CD39 and CD73 expressed on brain derived microglia in SIV infection contributes to ATP metabolism, suppresses T cell responses, and increase survival of microglia in vitro. We will measure and compare ectonucleotidase activities, the ability to suppress autologous SIV specific immune responses, and the sensitivity to ATP induced cell death, using CNS derived microglia from uninfected controls, SIV infected, and SIV infected rhesus macaques treated with cART. We anticipate that our proposed studies will provide a novel avenue for therapeutics to augment immune mediated clearance of HIV and other CNS pathogens.

描述（由申请方提供）：尽管接受了抗逆转录病毒治疗，CNS的HIV感染仍持续存在，这是神经系统疾病治疗的一个挑战，也是治疗患者根除HIV的一个重大障碍。很可能消除大脑中的HIV感染宿主将需要旨在刺激HIV感染细胞的免疫识别和/或规避免疫抑制机制的干预措施。三磷酸腺苷（ATP）是一种有效的免疫刺激剂，通过免疫细胞上的P2型受体起作用。相比之下，腺苷通过P1型受体对T细胞和巨噬细胞/树突状细胞具有有效的免疫抑制活性。CNS中的小胶质细胞，类似于调节性T细胞的作用，表达外核苷酸酶CD 39和CD 73，其将ATP和ADP转化为AMP（通过CD 39），并进一步代谢为腺苷（通过CD 73），提供了介导免疫调节的潜在重要机制。在我们对SIV感染的恒河猴CNS组织的初步研究中，CD 39和CD 73均表现出相对于未感染对照脑组织的表达增加。即使在没有脑炎的情况下，SIV感染脑中的实质小胶质细胞上的两种胞外酶的表达也显著增加。此外，CNS血管周围的巨噬细胞和小胶质细胞结节内的细胞在SIV脑炎的情况下高度表达这些酶。在我们提出的研究中，我们将检验这样的假设：在SIV感染的恒河猴的CNS中，ATP代谢通过小胶质细胞上的CD 39和CD 73表达的酶活性增加，有助于感染细胞的存活，并损害病毒特异性免疫应答。在特定目的I中，我们将检验小胶质细胞上的CD 39和CD 73表达在SIV感染中增加的假设，并确定cART治疗对表达和酶活性的影响。我们将在本研究过程中进一步评估作为CSF生物标志物的ATP代谢物，并确定这些值是否与SIV感染状态、发病机制的生物学和病毒学标志物、CNS中的CD 39和CD 73表达以及对cART治疗的应答相关。我们将检验在SIV感染中脑源性小胶质细胞上表达的增加的CD 39和CD 73有助于ATP代谢、抑制T细胞应答并增加体外小胶质细胞存活的假设。我们将测量和比较外核苷酸酶活性，抑制自体SIV特异性免疫应答的能力，以及对ATP诱导的细胞死亡的敏感性，使用来自未感染对照、SIV感染和用cART治疗的SIV感染恒河猴的CNS衍生的小胶质细胞。我们预计，我们提出的研究将提供一种新的途径，治疗，以增加免疫介导的清除艾滋病毒和其他中枢神经系统病原体。