Intrinsic Immunity and AIDS

内在免疫力和艾滋病

• 批准号: 8299503
• 负责人: Welkin E Johnson
• 金额: $ 55.99万
• 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/8299503
• 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）：TRIM 5基因编码TRIM 5a，一种赋予对逆转录病毒感染的内在抗性的胞质蛋白。自从TRIM 5a的抗逆转录病毒活性的最初描述以来，在主要的同行评审的艾滋病文献中已经出现了100多篇相关的出版物。然而，这些研究几乎完全集中在基于组织培养的测定中TRIM 5的抗病毒机制的结构/功能研究上。因此，令人惊讶的是，对TRIM 5在体内表达的调控、抑制机制或下游后果知之甚少。重要的是，我们实验室和至少一个其他小组发表的报告证明了TRIM 5表达对艾滋病猕猴模型中SIV感染的显着影响。此外，恒河猴TRIM 5的多态性变异仍然是HIV-1感染和疾病的真正动物模型的一个巨大障碍。这就提出了几个与艾滋病毒/艾滋病直接相关的关键问题，并对艾滋病的实验模型产生了具体的实际影响。找到这些问题的答案对于理解TRIM 5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。该研究计划是基于我们实验室发表的描述恒河猴TRIM 5基因座功能多态性及其对SIV感染的影响的数据。我们提出了三个具体目标，旨在1）充分评估TRIM 5介导的抑制对慢病毒感染和疾病进展的影响（第一特异性目的）; 2）确定IFN诱导的TRIM 5基因表达是否被SIV感染特异性改变（二）具体目标;和3）产生合理设计的HIV-1毒株，其能够在代表所有常见TRIM 5基因型的恒河猴的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将导致更好地了解TRIM 5在生物学相关的，在体内的情况下，而具体目标3的工作代表了一个关键的，但必要的一步，在一个实际的动物模型的HIV-1感染的方向。总之，这三个目标的工作将阐明TRIM 5介导的抑制的生物学相关性，并导致改进的艾滋病动物模型。