Immunoregulatory Function of Myelomonocytic Receptors in HIV-1 Infection

骨髓单核细胞受体在 HIV-1 感染中的免疫调节功能

• 批准号: 7554568
• 负责人: Xu Yu
• 金额: $ 44.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554568
• 关键词: Address; Affect; Alleles; Amino Acid Substitution; Antigen-Presenting Cells; Antigens; Antiviral Agents; Belief; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Communication; Cell physiology; Cells; Cellular Immunity; Chronic; Class; Clinical; Complex; Data; Data Set; Dendritic Cells; Dendritic cell activation; Depth; Development; Disease Progression; Epitopes; Evolution; Failure; Generations; Genetic; Goals; HIV-1; HIV-1 vaccine; Immune; Immune response; Immunity; Immunology; Immunosuppressive Agents; Individual; Infection; Investigation; Knowledge; Lead; Link; MHC Class I Genes; Mediating; Mutation; Pattern; Pattern Recognition; Peptide/MHC Complex; Peptides; Process; Progressive Disease; Property; Public Health; Reagent; Regulation; T-Lymphocyte; Testing; Thinking; Vaccine Design; Vaccines; Viral; Viremia; base; cytotoxic; design; immunogenicity; in vivo; interest; monocyte; novel; purge; receptor; response

DESCRIPTION (provided by applicant): HIV-1-specific T cell responses have strong antiviral activities and are therefore of particular interest for HIV-1 vaccine design. However, a deep understanding of immunoregulatory mechanisms that determine their evolution and function will be critical for their in vivo manipulation by vaccines and immunogens. Here, the PI proposes an entirely novel, previously unrecognized mechanism for the regulation of HIV-1 specific T cells through activating or inhibitory myelomonocytic MHC class I receptors on dendritic cells and monocytes. In her preliminary studies, the PI has found that HIV-1 CTL epitope/MHC class I complexes bind to these receptors in an antigenic peptide-specific fashion, thus suggesting an HIV-1 sequence- specific mechanism for the functional regulation of dendritic cells. Strikingly, the PI observed that HIV-1 CTL escape mutations can critically enhance the binding intensity of HIV-1 CTL epitope/ MHC class I complexes to inhibitory myelomonocytic MHC class I receptors and thus lead to a tolerogenic functional profile of dendritic cells, suggesting a connection between CTL epitope escape, altered recognition by myelomonocytic MHC class I receptors and functional changes of myelomonocytic cells. Based on these observations, the PI proposes to comprehensively assess binding properties of HIV-1 CTL epitope/MHC class I complexes to activating or inhibitory myelomonocytic receptors, how these interactions are affected by HIV-1 sequence evolution, and in which way these mechanisms result in functional alterations of dendritic cells and HIV-1- specific T cells. Moreover, the PI will test if associations between HLA class I alleles and HIV-1 disease progression correlate with specific patterns of recognition of these alleles by activating or inhibitory myelomonocytic receptors. Overall, these investigations open an entirely new perspective for the assessment of how HIV-1 can manipulate dendritic cells and ensuing HIV-1-specific T cells in a viral sequence-specific pattern by binding to myelomonocytic receptors and will thus be critical for HIV-1 vaccine design. PUBLIC HEALTH RELEVANCE: Dendritic cells can determine the functional profile of HIV-1-specific immune responses, and therefore are critical for HIV-1 vaccine design. In the proposed studies, the PI will analyze how HIV-1 viral sequence evolution can affect the functional activity of dendritic cells through interactions with myelomonocytic receptors. These investigations will be crucial for identifying correlates of protective immunity against HIV-1, and ultimately developing effective HIV-1 vaccines.

描述（由申请方提供）：HIV-1特异性T细胞应答具有强抗病毒活性，因此对HIV-1疫苗设计特别感兴趣。然而，深入了解决定其进化和功能的免疫调节机制对于疫苗和免疫原的体内操作至关重要。在这里，PI提出了一种全新的，以前未被认识的机制，通过激活或抑制树突状细胞和单核细胞上的骨髓单核细胞MHC I类受体来调节HIV-1特异性T细胞。在她的初步研究中，PI已经发现HIV-1 CTL表位/MHC I类复合物以抗原肽特异性方式结合这些受体，从而表明树突状细胞功能调节的HIV-1序列特异性机制。值得注意的是，PI观察到HIV-1 CTL逃逸突变可显著增强HIV-1 CTL表位/ MHC I类复合物与抑制性骨髓单核细胞MHC I类受体的结合强度，从而导致树突状细胞的致耐受性功能特征，表明CTL表位逃逸、骨髓单核细胞MHC I类受体识别改变和骨髓单核细胞功能变化之间存在联系。基于这些观察结果，PI建议全面评估HIV-1 CTL表位/MHC I类复合物与激活或抑制性骨髓单核细胞受体的结合特性，这些相互作用如何受到HIV-1序列进化的影响，以及这些机制如何导致树突状细胞和HIV-1特异性T细胞的功能改变。此外，PI将检测HLA I类等位基因与HIV-1疾病进展之间的关联是否与这些等位基因通过激活或抑制骨髓单核细胞受体识别的特定模式相关。总的来说，这些研究为评估HIV-1如何通过与骨髓单核细胞受体结合以病毒序列特异性模式操纵树突状细胞和随后的HIV-1特异性T细胞开辟了一个全新的视角，因此对于HIV-1疫苗设计至关重要。 公共卫生关系：树突状细胞可以决定HIV-1特异性免疫反应的功能，因此对HIV-1疫苗设计至关重要。在拟议的研究中，PI将分析HIV-1病毒序列进化如何通过与骨髓单核细胞受体的相互作用影响树突状细胞的功能活性。这些研究对于确定针对HIV-1的保护性免疫的相关性以及最终开发有效的HIV-1疫苗至关重要。