Molecular basis of myelomonocytic receptor function in HIV-1 infection

HIV-1感染中骨髓单核细胞受体功能的分子基础

• 批准号: 7994142
• 负责人: ERIC JOHN SUNDBERG
• 金额: $ 18.66万
• 依托单位: BOSTON BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2011-04-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994142
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affinity; Alanine; Alleles; Amino Acid Substitution; Anti-Retroviral Agents; Antigen-Presenting Cells; Antigens; Antiviral Agents; Binding; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Communication; Cell physiology; Cell surface; Cells; Cellular Immunity; Chronic; Clinical; Complex; Country; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Engineering; Epitopes; Event; Evolution; Failure; Generations; Genetic; Goals; HIV-1; HLA Antigens; Human; Immune; Immune response; Immunology; Immunosuppressive Agents; Individual; Infection; Kinetics; Knowledge; Lead; Link; Lymphocyte; MHC Class I Genes; Major Histocompatibility Complex; Molecular; Mutagenesis; Mutation; Peptide/MHC Complex; Peptides; Play; Population; Progressive Disease; Property; Proteins; Reagent; Relative (related person); Roentgen Rays; Role; Scanning; Specificity; Structure; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Techniques; Therapeutic; Thermodynamics; Vaccine Design; Vaccines; Variant; Viral; Viremia; Virus; Work; Yeasts; base; combinatorial; design; directed evolution; global health; immunogenicity; improved; in vivo; innovation; insight; leukocyte antigen typing; meetings; monocyte; mutant; novel; public health relevance; receptor; receptor binding; receptor function; success

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.

描述（由申请人提供）：HIV-1感染中脊髓细胞受体功能的分子基础摘要摘要利用人类免疫缺陷病毒（HIV）-1特异性T细胞的有效抗病毒活性对于有效的HIV HIV-1疫苗和免疫原子的设计和开发至关重要。为此，需要对影响这些细胞的进化和免疫调节功能的精确分子机制有清晰的了解。在先前的协作工作中，PI和Co-Pi发现了一种用于HIV-1特异性T细胞的新型调节机制，该机制取决于抑制性的相互作用和激活脊髓细胞主要的组织相容性复合物I类（MHC-I）受体在树突状细胞上与HIV-1 cytototoxic complipe-emplocyte（MHC-I）受体（MHC-I）受体（MHC-I）受体（MHC-I）受体。我们已经发现（i）这些分子之间的结合是抗原肽和人白细胞抗原（HLA）等位基因 - 特异性的，（ii）HIV-1 CTL逃生突变会增加肽/MHC-I（PMHC-I）促成抑制性髓细胞受体I的亲密关系，从而成为抑制性脊髓细胞的II型细胞，从已知在人类中具有HIV-1保护的等位基因与相对亲和力增加的激活脊髓细胞受体。通过这些方式，也许还有其他方式，脊髓细胞受体在对HIV-1病毒血症的适应性免疫反应中起着关键和以前未被认可的免疫调节作用。在这里，我们建议确定PMHC-I/脊髓细胞受体相互作用的分子基础，并且对这些结合事件的有针对性操纵将导致新颖和改善的HIV-1疫苗和免疫原子。我们旨在确定PMHC-I/脊髓细胞受体相互作用中分子特异性的综合结构，能量和功能基础，以便为在HIV-1疫苗中包括特定的肽表位和工程亲和力亲和力成熟的骨髓细胞受体变种对ACT ACT ACT AS HIV-1免疫类球体提供明确的合理性。 公共卫生相关性：HIV-1感染中脊髓细胞受体功能的分子基础，目前有超过3000万人感染了人类免疫缺陷病毒（HIV）-1 -1全球，仅在2007年，仅在2007年，仅270万个患者就会感染该病毒，再加上2000万人死于艾滋病。尽管存在相对有效的抗逆转录病毒疗法，但仅在第一世界国家就可以广泛使用，而大约95％的HIV-1感染者居住在发展中国家，因此，有效的HIV-1疫苗的发展仍然是全球健康的目标。我们提出的研究旨在阐明关键分子机制，通过该机制，HIV-1感染在人类中进展以推动HIV-1疫苗设计中的创新以及工程新型蛋白质基于蛋白质的疗法来抵消HIV-1感染。