Protective roles of CTL responses to HIV-1 associated self epitope

CTL 对 HIV-1 相关自身表位反应的保护作用

• 批准号: 7790553
• 负责人: Beth Deirdre Jamieson-Karavodin
• 金额: $ 15.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790553
• 关键词: Acquired Immunodeficiency Syndrome; Antigens; Attention; Autoantigens; Autologous Dendritic Cells; Back; CD8B1 gene; Cancer Patient; Cells; Data; Dendritic Cells; Disease Progression; Epitopes; HIV; HIV-1; HLA A*0201 antigen; Heat shock proteins; Immune; Immune response; Immunologics; In Vitro; Individual; Infection; Investigation; Mediating; Mutation; NK cell receptor NKB1; Natural Immunity; Pathogenesis; Patients; Peptides; Personal Communication; Physiologic pulse; Physiological; Play; Process; Proteins; Public Health; Role; Surface; System; T-Lymphocyte; Testing; Therapeutic; Tumor Antigens; Up-Regulation; Viral Antigens; Viremia; design; in vivo; melanoma; monocyte; protective effect; public health relevance; research study; response; stress protein; therapeutic development; therapeutic target; tumor

DESCRIPTION (provided by applicant): HLA-B*5701 is associated with slow progression to AIDS. While much attention has focused on the HLA- B*5701 restricted presentation of HIV-1 encoded epitopes to CD8+ T-cells, it remains unclear how HLA- B*5701 exerts it protective influence. In this proposal, we will explore the potential role of HLA-B*5701 presentation of self-epitopes derived from HIV-1 infected cells in controlling HIV-1 infection. Like other viruses, HIV-1 infection of a cell can increase the surface presentation of HLA-class I restricted self-epitopes. As part of the physiological response to stress, proteins become quickly up-regulated and degraded resulting in an altered repertoire of self-epitope presentation by the infected cell. While this phenomenon is well documented, the role played by presentation of self-epitopes in the overall immune response to HIV-1 infection and long-term protection of the host are completely unknown. The up-regulation of tumor-specific antigens, such as MART 1, is a process that has been capitalized upon for the design of therapeutic strategies. CD8+ T-cells from the cancer patient are cultured in vivo with autologous dendritic cells pulsed with peptides representing the tumor-specific epitope then infused back into the patient in an adoptive therapy strategy to augment ongoing CTL responses. Together these data indicate that further exploration is warranted into the role of self- epitopes in determining the rate of HIV-1 disease progression and as a potential target for therapeutic strategies to eradicate HIV-1 infected cells. Experiments within this proposal will test our hypothesis that CTL responses to self-antigens play a significant role in the overall long-term immunologic control of HIV-1 viremia by augmenting existing CTL responses to viral antigens. To test this hypothesis, we intend to: Aim 1) Characterize HLA-B*5701 restricted self-epitopes up-regulated by HIV-1 infection, Aim2) Investigate whether self epitopes, elicited by HIV-1 infection, generate HLA-restricted CTL in vivo, and Aim 3) Evaluate CTL functions of in vitro primed HLA-A*0201, and HLA-B*5701 restricted self-epitope-specific CD8+ T-cells by peptide pulsed monocyte derived dendritic cells. PUBLIC HEALTH RELEVANCE: The experiments could benefit HIV-1 infected individuals by providing a unique avenue for the development of therapeutic strategies.

描述（由申请人提供）：HLA-B*5701与艾滋病的缓慢进展有关。虽然许多注意力集中在HLA- B*5701限制性地将HIV-1编码的表位呈递给CD 8 + T细胞，但仍不清楚HLA- B*5701如何发挥其保护性影响。在本研究中，我们将探讨HLA-B*5701呈递来自HIV-1感染细胞的自身表位在控制HIV-1感染中的潜在作用。像其他病毒一样，HIV-1感染细胞可以增加HLA-I类限制性自身表位的表面呈递。作为对应激的生理反应的一部分，蛋白质变得快速上调和降解，从而导致受感染细胞的自身表位呈递的库改变。虽然这种现象是有据可查的，但自我表位的呈递在对HIV-1感染的整体免疫应答和对宿主的长期保护中所起的作用是完全未知的。肿瘤特异性抗原（例如MART 1）的上调是一种已被用于设计治疗策略的过程。将来自癌症患者的CD 8 + T细胞与用代表肿瘤特异性表位的肽脉冲的自体树突细胞一起在体内培养，然后以过继治疗策略输注回患者体内以增强正在进行的CTL应答。总之，这些数据表明，有必要进一步探索自身表位在确定HIV-1疾病进展速率中的作用，以及作为根除HIV-1感染细胞的治疗策略的潜在靶点。本提案中的实验将验证我们的假设，即对自身抗原的CTL反应通过增强现有的对病毒抗原的CTL反应，在HIV-1病毒血症的整体长期免疫控制中发挥重要作用。为了检验这一假设，我们打算：目的1）鉴定HIV-1感染后上调的HLA-B*5701限制性自身表位，目的2）研究HIV-1感染后诱导的自身表位是否在体内产生HLA限制性CTL，目的3）评价体外致敏的HLA-A*0201的CTL功能，和HLA-B*5701限制性自身表位特异性CD 8 + T细胞。公共卫生关系：这些实验可以通过为治疗策略的开发提供独特的途径而使HIV-1感染者受益。