Molecular basis of myelomonocytic receptor function in HIV-1 infection

说明书(申请人提供)：粒单核细胞受体在HIV-1感染中作用的分子基础摘要利用人类免疫缺陷病毒(HIV)-1特异性T细胞的强大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确切分子机制。在以前的合作中，PI和co-PI发现了一种新的HIV-1特异性T细胞的调节机制，该机制依赖于树突状细胞和单核细胞上抑制和激活的MHC-I受体与HIV-1细胞毒性T淋巴细胞(CTL)表位/MHC-I复合体的相互作用。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-1CTL逃逸突变增加了抑制性髓单核细胞受体(pMHC-I)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HLAI类等位基因与激活的髓单核细胞受体结合的相对亲和力增加。在这些方面，或许还有其他方面，单核细胞受体在针对HIV-1病毒血症的获得性免疫反应中发挥着关键的、以前未被认识到的免疫调节作用。在这里，我们建议确定pMHC-I/粒单核细胞受体相互作用的分子基础，以及对这些结合事件的靶向操作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/粒单核细胞受体相互作用中分子特异性的全面的结构、能量和功能基础，以便为将特定的多肽表位纳入HIV-1疫苗提供明确的理论依据，并设计亲和力成熟的粒单核细胞受体变异体作为HIV-1免疫原。 公共卫生相关性：粒单核细胞受体在HIV-1感染中作用的分子基础目前全世界有3000多万人感染了人类免疫缺陷病毒(HIV)-1，仅在2007年就有270万人感染了该病毒，另有200万人死于艾滋病。虽然存在相对有效的抗逆转录病毒疗法，但这种疗法仅在第一世界国家广泛可用，约95%的艾滋病毒-1感染者生活在发展中国家，因此，开发有效的艾滋病毒-1疫苗仍然是一个突出的全球卫生目标。我们提出的研究旨在阐明HIV-1感染在人类中进展的关键分子机制，以推动HIV-1疫苗设计的创新，并设计新的基于蛋白质的疗法来对抗HIV-1感染。

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. PUBLIC HEALTH RELEVANCE: Molecular basis of myelomonocytic receptor function in HIV-1 infection More than 30 million individuals are currently infected with human immunodeficiency virus (HIV)-1 worldwide, and in the year 2007 alone 2.7 million additional individuals were infected with the virus and a further 2 million individuals died of AIDS. While relatively effective anti-retroviral therapy exists, it is widely available only in first world countries, and some 95 percent of HIV-1-infected individuals reside in the developing world, and thus, the development of an effective HIV-1 vaccine remains an outstanding global health goal. Our proposed studies are aimed at elucidating critical molecular mechanisms by which HIV-1 infection progresses in humans to drive innovation in HIV-1 vaccine design and at engineering novel protein-based therapeutics to counteract HIV-1 infection.