Molecular basis of myelomonocytic receptor function in HIV-1 infection

摘要利用人类免疫缺陷病毒(HIV)-1特异性T细胞的强效抗病毒活性对于设计和开发有效的HIV-1疫苗和免疫原至关重要。要做到这一点，需要清楚地了解影响这些细胞进化和免疫调节功能的精确分子机制。在之前的合作工作中，PI和co-PI发现了HIV-1特异性T细胞的一种新的调节机制，该机制依赖于树突状细胞和单核细胞上具有HIV-1细胞毒性T淋巴细胞（CTL）表位/MHC-I复合物的抑制和激活髓单核细胞主要组织相容性复合体I类（MHC-I）受体的相互作用。我们发现(i)这些分子之间的结合是抗原肽和人类白细胞抗原（HLA）等位基因特异性的，（ii） HIV-1 CTL逃逸突变增加了肽/MHC-I （pMHC-I）对抑制髓细胞受体的亲和力，导致树突状细胞变得耐受，（iii）已知在人类中具有HIV-1保护作用的HLA i类等位基因与激活髓细胞受体结合的相对亲和力增加。通过这些方式，或许还有其他方式，髓细胞受体在HIV-1病毒血症的适应性免疫反应中发挥了关键的、以前未被认识到的免疫调节作用。在这里，我们提出确定pMHC-I/髓单胞细胞受体相互作用的分子基础，并有针对性地操纵这些结合事件将导致新的和改进的HIV-1疫苗和免疫原。我们的目标是确定pMHC-I/骨髓单核细胞受体相互作用分子特异性的全面结构、能量和功能基础，以便为在HIV-1疫苗中加入特异性肽表位提供明确的理性依据，并设计亲和成熟的骨髓单核细胞受体变体作为HIV-1免疫原。

DESCRIPTION (provided by applicant): Molecular basis of myelomonocytic receptor function in HIV-1 infection ABSTRACT Harnessing the potent antiviral activities of human immunodeficiency virus (HIV)-1-specific T cells is critical to the design and development of effective HIV-1 vaccines and immunogens. To do so, a clear understanding of the precise molecular mechanisms that influence the evolution and immunoregulatory function of these cells is needed. In previous collaborative work, the PI and co-PI discovered a novel regulatory mechanism for HIV-1-specific T cells, which depends on the interactions of inhibitory and activating myelomonocytic major histocompatibility complex class I (MHC-I) receptors on dendritic cells and monocytes with HIV-1 cytotoxic T lymphocyte (CTL) epitope/MHC-I complexes. We have found (i) that binding between these molecules is both antigenic peptide- and human leukocyte antigen (HLA) allele- specific, (ii) that HIV-1 CTL escape mutations increase peptide/MHC-I (pMHC-I) affinities for inhibitory myelomonocytic receptors causing dendritic cells to become tolerogenic, and (iii) that HLA class I alleles that are known to be HIV-1-protective in humans bind activating myelomonocytic receptors with increased relative affinities. In these ways, and perhaps others, myelomonocytic receptors play key and previously unrecognized immunoregulatory roles in the adaptive immune response to HIV-1 viremia. Here, we propose that determining the molecular basis of pMHC-I/myelomonocytic receptor interactions and that the targeted manipulation of these binding events will lead to novel and improved HIV-1 vaccines and immunogens. We aim to determine a comprehensive structural, energetic and functional basis for molecular specificity in pMHC-I/myelomonocytic receptor interactions in order to provide a clear rational for including specific peptide epitopes in HIV-1 vaccines and to engineer affinity-matured myelomonocytic receptor variants to act as HIV-1 immunogens.