Immunoregulatory Function of Myelomonocytic Receptors in HIV-1 Infection

描述(由申请人提供)：HIV-1特异性T细胞反应具有很强的抗病毒活性，因此对HIV-1疫苗的设计特别感兴趣。然而，深入了解决定其进化和功能的免疫调节机制将对疫苗和免疫原在体内操纵它们至关重要。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粒单核细胞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发现HIV-1 CTL表位/MHC I类复合体以抗原肽特异性的方式与这些受体结合，从而暗示了HIV-1序列特异性的树突状细胞功能调节机制。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类复合体与抑制的粒-单核细胞MHC-I受体的结合强度，从而导致树突状细胞的耐受功能谱，提示CTL表位逃逸、粒-单核细胞MHC-I受体识别改变与粒-单核细胞功能改变之间存在联系。基于这些观察，PI建议全面评估HIV-1 CTL表位/MHC I类复合体与激活或抑制粒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细胞的功能变化。此外，PI将测试人类白细胞抗原I类等位基因与HIV-1疾病进展之间的关联是否与通过激活或抑制粒单核细胞受体识别这些等位基因的特定模式相关。总体而言，这些研究为评估HIV-1如何通过与粒单核细胞受体结合，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，因此将对HIV-1疫苗的设计至关重要。 公共卫生相关性：树突状细胞可以确定HIV-1特异性免疫反应的功能特征，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粒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因素以及最终开发有效的HIV-1疫苗至关重要。

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.