Immunoregulatory networks and HIV pathogenesis

免疫调节网络和艾滋病毒发病机制

• 批准号: 8515500
• 负责人: Daniel E Kaufmann
• 金额: $ 25.7万
• 依托单位: UNIVERSITY OF MONTREAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515500
• 关键词: AIDS clinical trial group; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Activities of Daily Living; Adjuvant; Affect; Animal Model; Antigen-Presenting Cells; Antiviral Therapy; Area; Autologous; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular biology; Characteristics; Chronic; Clinical; Complement; Data; Defect; Development; Disease; Employee Strikes; Epigenetic Process; Event; Failure; Fostering; Functional disorder; Funding; Gene Expression Profile; Genes; Goals; Grant; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Image; Immune response; Immunity; Impairment; Individual; Inflammatory; Interferons; Interleukin-10; Interleukin-2; Intervention; Knowledge; Lead; Leukocytes; Licensing; Life; Ligands; Lymphoid Tissue; Maintenance; Mediating; Molecular; Molecular Immunology; Morbidity - disease rate; Pathogenesis; Pathway interactions; Persons; Phenotype; Play; Quality of life; Regulatory Pathway; Reporting; Research; Role; Signal Transduction; Staging; T cell differentiation; T cell response; T-Lymphocyte; TNFSF5 gene; Treatment Protocols; Vaccine Design; Viral; Virus; Virus Diseases; antiretroviral therapy; base; cellular imaging; cytokine; demethylation; design; exhaust; exhaustion; feeding; fighting; human disease; immunological synapse; immunological synapse formation; improved; inhibitor/antagonist; mortality; neglect; new therapeutic target; novel; novel therapeutics; overexpression; peripheral blood; prevent; programs; prophylactic; receptor; response; restoration; success; synaptic function; synaptogenesis; therapeutic target; therapy development; transcription factor; vaccine candidate

DESCRIPTION (provided by applicant): Combination antiretroviral therapy (ART) has resulted in a major decrease in morbidity and mortality in HIV- infection. However, ART does not eradicate virus or restore HIV-specific immune responses capable of controlling viral replication once therapy is interrupted. Development of interventions that could generate immune responses capable of maintaining HIV suppression after cessation of ART and improve efficacy of vaccine candidates would be a crucial clinical advance. Evidence suggests that effective HIV-specific CD4 T cells will be required to achieve this goal, yet these cells remain seriously understudied. The lack of restoration of effective HIV-specific CD4 T helper responses in spite of extended ART raised the possibility that these responses are irreversibly crippled. However, the results we have generated during the first four years of this grant support a striking conclusion: that CD4 T cell impairment in HIV-infection is to a significant extent under control of inhibitory mechanisms that can be reverted by manipulation of regulatory networks. Data suggest that one of these pathways, PD-1, also plays an important role in the maintenance of HIV reservoirs, making it a very attractive therapeutic target. In this competing renewal we propose to build on the major progress made during the initial funding period and to utilize combined approaches of cellular biology, molecular immunology and advanced cell imaging to pinpoint critical events that regulate effective and inefficient HIV-specific CD4 T cell responses. We also propose to investigate another neglected area of HIV-research: the impact that ineffective HIV-specific CD4 T cell responses have on antigen-presenting cell functions. In Aim 1, we will identify critical gene signatures of functional and exhausted HIV-specific CD4 T cells. We will determine the master transcription factors that are regulated by PD-1 in HIV-specific CD4 T cells and define their role in the control of exhausted CD4 T cell functions. We will examine the potential for HIV-specific CD4 T cell functional plasticity by overexpressing or silencing these master genes in primary cells. In Aim 2 we will use advanced live imaging to determine the dynamics of immunological synapses built by functional and exhausted HIV- specific CD4 T cells. We will define the role of individual co-inhibitors and determine whether optimized co- stimulatory signaling can prevent this defective synapse formation and function. In Aim 3 we will define specific defects in licensing of antigen-presenting cells by HIV-specific CD4 T cells, and specific mechanisms of APC impairment. We will determine whether APC present inappropriate responses to stimulatory signals. By selectively blocking molecules expressed by dysfunctional CD4 T cells, we will determine events causally involved in the perturbation of APC functions. We will also define how the interplay between regulatory pathways leads to the observed defects. This proposal will provide novel understanding of the molecular basis for functional differences between protective and ineffective HIV-specific CD4 T cells and will identify new therapeutic targets to generate effective HIV-specific immunity in ART-treated and uninfected persons.

描述（由申请人提供）：联合抗逆转录病毒治疗（ART）导致艾滋病毒感染的发病率和死亡率大幅下降。然而，抗逆转录病毒治疗一旦中断，就不能根除病毒或恢复能够控制病毒复制的艾滋病毒特异性免疫反应。开发干预措施，产生能够在停止抗逆转录病毒治疗后维持艾滋病毒抑制的免疫反应，并提高候选疫苗的效力，将是一项至关重要的临床进展。有证据表明，要实现这一目标，需要有效的hiv特异性CD4 T细胞，但对这些细胞的研究仍严重不足。尽管进行了广泛的抗逆转录病毒治疗，但缺乏有效的hiv特异性CD4 T辅助反应的恢复，这增加了这些反应被不可逆转地削弱的可能性。然而，我们在这项资助的头四年中所产生的结果支持了一个惊人的结论：hiv感染中的CD4 T细胞损伤在很大程度上是可控的