Activation-induced Non-responsiveness causes HIV Prog.

激活引起的无反应会导致 HIV 进展。

• 批准号: 7574710
• 负责人: HELEN HORTON
• 金额: $ 9.9万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574710
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; Acquired Immunodeficiency Syndrome; Address; Alleles; Anti-Retroviral Agents; Antigens; Apoptosis; Appearance; Autologous; Avidity; Biological Assay; CD8B1 gene; Cell Maturation; Cells; Characteristics; Chronic; Clonal Expansion; Color; Data; Disease; Disease Progression; Down-Regulation; Epitopes; Evolution; Flow Cytometry; Frequencies; HIV; HIV vaccine; HIV-1; HLA-A3 Antigen; HLA-B27 Antigen; IL2 gene; IL4 gene; Immune; Immune response; In Vitro; Individual; Infection; Infection Control; Interferon Type II; Interleukin-10; Interleukin-2; Interleukin-4; Lead; Ligation; Link; MHC Class I Genes; Measures; Modeling; Mus; Mutation; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Proliferating; Proteins; Proteomics; Research Personnel; Resistance; Sampling; Sorting - Cell Movement; Specificity; T-Cell Activation; T-Lymphocyte; TCR Activation; Technology; Testing; Therapeutic Intervention; Time; Tumor Immunity; Vaccination; Viral; Virus; Virus Diseases; Virus Replication; anergy; cell mediated lymphocytolysis test; cytokine; design; in vivo; pressure; prevent; programs; prophylactic; receptor; response; therapeutic vaccine

DESCRIPTION (provided by applicant): The immune correlates of protection against HIV-1 are unknown making rationale design of efficacious, prophylactic and therapeutic vaccines difficult. This proposal will investigate whether induction of Activation- Induced Non-Responsiveness (AINR) in HIV-specific CD8+T cells leads to disease progression in persons chronically infected with HIV-1. Our preliminary data show that chronic infection with HIV-1 leads to the induction of AINR in HIV-specific T cells. Furthermore, individuals who are controlling chronic HIV-1 infection (long term non-progressors, LTNP) possess HIV-specific T cells that are resistant to AINR. Thus, induction of AINR in HIV-specific CD8+ T cells may be the cause of loss of viral control and progression to AIDS. In Aim 1 we will characterize the functional phenotype of AINR CD8+ HIV-specific T cells to determine which effector functions (apart from proliferative ability) are compromised in the AINR sate using IFN-gamma ELISpot, polychromatic (11 color) flow cytometry and proteomics technologies. Furthermore, longitudinal analysis of these T cell responses throughout the course of infection will allow us to determine when AINR appears in the context of natural infection and whether appearance of AINR CD8+ T cells correlates with disease progression. In Aim 2, we will determine whether HIV-specific AINR CD8+ T cells are compromised in their ability to prevent viral replication using in vitro infectivity assays. We will ascertain whether the presence of AINR HIV-specific T cells in vivo influences viral evolution by sequencing regions of the autologous virus that correspond to epitopes recognized by AINR CD8+ T cells. In addition, we will attempt to reverse the AINR state and determine if this leads to enhanced control of viral infection. In Aim 3, we will identify factors that contribute to induction of AINR. Since the proposed studies will potentially characterize an immune correlate of protection from HIV-1 disease progression they will have far reaching implications on therapeutic intervention in chronically-infected individuals and rationale design of HIV vaccines.

描述（由申请人提供）：针对HIV-1的免疫相关性是未知的，因此难以对有效，预防性和治疗性疫苗的理由设计。该建议将研究HIV特异性CD8+T细胞中激活诱导的无反应性（AINR）是否导致长期感染HIV-1的人的疾病进展。我们的初步数据表明，HIV-1的慢性感染导致HIV特异性T细胞中AINR的诱导。此外，控制了慢性HIV-1感染（长期非培训器LTNP）的个体具有对AINR抗药性的HIV特异性T细胞。因此，HIV特异性CD8+ T细胞中AINR的诱导可能是病毒控制和进展为AIDS的原因。在AIM 1中，我们将使用IFN-Gamma ELISPOT，多染色（11颜色）流动细胞仪和蛋白质组学技术在AINR SATE中损害AINR CD8+ HIV特异性T细胞AINR CD8+ HIV特异性T细胞的功能表型。此外，在整个感染过程中对这些T细胞反应的纵向分析将使我们能够确定AINR何时出现在自然感染的背景下，以及AINR CD8+ T细胞的出现是否与疾病进展相关。在AIM 2中，我们将确定HIV特异性AINR CD8+ T细胞是否在使用体外感染性测定的能力方面损害了其预防病毒复制的能力。我们将确定在体内的AINR HIV特异性T细胞的存在是否通过对aINR CD8+ T细胞识别的表位的自体病毒的测序区域的测序区域来影响病毒进化。此外，我们将尝试逆转AINR状态，并确定这是否导致对病毒感染的控制。在AIM 3中，我们将确定有助于诱导AINR的因素。由于拟议的研究将有潜在地表征保护免受HIV-1疾病进展的免疫相关性，因此它们将对慢性感染个体的治疗干预和HIV疫苗的理由设计具有很大的影响。