Intrinsic Immunity and AIDS

内在免疫力和艾滋病

基本信息

批准号：
8690754
负责人：
Welkin E Johnson
金额：
$ 67.06万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
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/8690754
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

项目摘要

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，这是一种赋予逆转录病毒感染固有耐药性的胞质蛋白。自从TRIM5A的抗逆转录病毒活性的最初描述以来，已经出现了由同行评审的艾滋病文献中出现的一百多个相关出版物。但是，这些研究几乎仅专注于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，对体内Trim5表达的调节，抑制作用或下游后果的调节，几乎没有知识。至关重要的是，我们实验室和另一组至少一组的报告表明，TRIM5表达对猕猴艾滋病模型中SIV感染的显着影响。此外，恒河猕猴Trim5的多态性变化仍然是HIV-1感染和疾病的真正动物模型的巨大障碍。这引发了几个至关重要的问题，与艾滋病毒/艾滋病直接相关，并具有对艾滋病实验模型的特定实际含义。找到这些问题的答案对于理解TRIM5的体内生物学基本生物及其与临床前艾滋病研究的特定相关性至关重要。该研究计划基于来自我们实验室的已发表数据，描述了恒河猕猴Trim5基因座中的功能多态性及其对SIV感染的影响。我们提出了三个特定目标，旨在1）充分评估TIM5介导的抑制对慢病毒感染和疾病进展的影响（第一个特定目的）； 2）确定IFN诱导的TRIM5基因表达是否通过SIV感染特异性改变（第二个特定目的）； 3）生成理性设计的HIV-1菌株，能够在代表所有常见TRIM5基因型的恒河猕猴中鲁棒复制（第三个特定目的）。特定的目标1和特定目标2将在生物学相关的体内环境中更好地理解TRIM5，而在特定目标3上的工作代表了在HIV-1感染的实用动物模型的方向上的关键但必要的步骤。共同处理这三个目标将阐明TRIM5介导的抑制的生物学相关性，并导致改善的艾滋病动物模型。