Intrinsic Immunity and AIDS

内在免疫力和艾滋病

• 批准号: 8493987
• 负责人: Welkin E Johnson
• 金额: $ 52.63万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493987
• 关键词: AIDS Vaccines; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Alleles; Animal Model; Animals; Anti-Retroviral Agents; Antiviral Agents; Binding; Biological; Biological Assay; Biology; CD4 Positive T Lymphocytes; Capsid; Capsid Proteins; Cell Line; Cells; Chronic; Coupling; Cytoplasm; Data; Detection; Development; Disease; Disease Progression; Dose; Experimental Models; Exposure to; Future; Gene Expression; Generations; Genes; Genetic Polymorphism; Genotype; HIV; HIV Infections; HIV-1; HIV-2; Health; Homologous Gene; Human; Immune; Immune response; Immunity; In Vitro; Infection; Interferons; Kinetics; Laboratories; Lead; Lentivirus Infections; Literature; Macaca; Macaca mulatta; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutation; Outcome; Pathogenesis; Pattern; Pattern recognition receptor; Peer Review; Peripheral Blood Mononuclear Cell; Play; Predisposition; Proteins; Publications; Publishing; Regulation; Relative (related person); Reporting; Research; Resistance; Retroviridae; Role; SIV; Sampling; Specificity; Structure; T-Lymphocyte; Vaccines; Variant; Viral; Virus; Virus Diseases; Work; base; design; improved; in vivo; mRNA Expression; macrophage; mutant; nonhuman primate; novel; pathogen; pre-clinical; research study; response; simian human immunodeficiency virus; success; tissue culture; transmission process

DESCRIPTION (provided by applicant): The TRIM5 gene encodes TRIM5a, a cytosolic protein that confers intrinsic resistance to retroviral infection. Since the initial description of the antiretroviral activity of TRIM5a, over one hundred related publications have appeared in the primary, peer-reviewed AIDS literature. However, these studies have focused almost exclusively on structure/function studies of TRIM5's antiviral mechanism in tissue culture based assays. Thus, surprisingly little is known about the regulation, mechanisms of suppression or downstream consequences of TRIM5 expression in vivo. Critically, published reports from our lab and at least one other group demonstrate a significant impact of TRIM5 expression on SIV infection in macaque models of AIDS. Moreover, polymorphic variation in rhesus macaque TRIM5 remains as a formidable obstacle to a true animal model of HIV-1 infection and disease. This raises several crucial questions with direct relevance to HIV/AIDS and with specific practical implications for experimental models of AIDS. Finding answers to these questions is essential to understanding both the fundamental in vivo biology of TRIM5 and its specific relevance to preclinical AIDS research. The research plan is based on published data from our laboratory describing functional polymorphism in the rhesus macaque TRIM5 locus, and its influence on SIV infection. We propose three specific aims, designed to 1) fully assess the impact of TRIM5-mediated suppression on lentiviral infection and disease progression (first Specific Aim); 2) determine whether IFN-inducible TRIM5 gene expression is specifically altered by SIV infection (second Specific Aim); and 3) generate rationally designed HIV-1 strains capable of robust replication in primary cells of rhesus macaques representing all common TRIM5 genotypes (third Specific Aim). Specific Aim 1 and Specific Aim 2 will lead to a better understanding of TRIM5 in a biologically relevant, in vivo context, while work on Specific Aim 3 represents a critical but necessary step in the direction of a practical animal model of HIV-1 infection. Together, work on these three aims will illuminate the biological relevance of TRIM5- mediated suppression and lead to improved animal models of AIDS.

描述（由申请人提供）：TRIM5基因编码TRIM5a，一种赋予逆转录病毒感染内在抵抗力的胞浆蛋白。自从首次描述 TRIM5a 的抗逆转录病毒活性以来，经过同行评审的主要艾滋病文献中已经出现了一百多篇相关出版物。然而，这些研究几乎完全集中在基于组织培养的测定中 TRIM5 抗病毒机制的结构/功能研究。因此，令人惊讶的是，人们对 TRIM5 体内表达的调节、抑制机制或下游后果知之甚少。至关重要的是，我们实验室和至少另一个小组发表的报告表明，TRIM5 表达对艾滋病猕猴模型中的 SIV 感染具有显着影响。此外，恒河猴TRIM5的多态性变异仍然是HIV-1感染和疾病的真实动物模型的巨大障碍。这就提出了几个与艾滋病毒/艾滋病直接相关的关键问题，并对艾滋病实验模型具有具体的实际意义。找到这些问题的答案对于理解 TRIM5 的基本体内生物学及其与临床前艾滋病研究的具体相关性至关重要。该研究计划基于我们实验室公布的数据，描述了恒河猴 TRIM5 位点的功能多态性及其对 SIV 感染的影响。我们提出了三个具体目标，旨在1）全面评估TRIM5介导的抑制对慢病毒感染和疾病进展的影响（第一个具体目标）； 2) 确定 IFN 诱导型 TRIM5 基因表达是否因 SIV 感染而发生特异性改变（第二个具体目标）； 3) 产生合理设计的 HIV-1 毒株，能够在代表所有常见 TRIM5 基因型的恒河猴原代细胞中稳健复制（第三个具体目标）。具体目标 1 和具体目标 2 将有助于在生物学相关的体内环境中更好地理解 TRIM5，而具体目标 3 的工作则代表着朝着 HIV-1 感染的实用动物模型方向迈出关键但必要的一步。这三个目标的共同努力将阐明 TRIM5 介导的抑制的生物学相关性，并导致改进艾滋病动物模型。