Intrinsic Immunity and AIDS

描述（由申请人提供）：TRIM5基因编码TRIM5a，这是一种胞质蛋白，赋予对逆转录病毒感染的内在抗性。自从对TRIM5a抗逆转录病毒活性的最初描述以来，已有一百多篇相关的出版物出现在主要的同行评议的艾滋病文献中。然而，这些研究几乎完全集中在基于组织培养的检测中TRIM5抗病毒机制的结构/功能研究。因此，我们对TRIM5在体内表达的调控、抑制机制或下游后果知之甚少。至关重要的是，我们实验室和至少一个其他小组发表的报告表明，TRIM5表达对艾滋病猕猴模型中SIV感染的显著影响。此外，恒河猴TRIM5的多态性变异仍然是建立HIV-1感染和疾病的真正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，并对艾滋病的实验模型具有具体的实际影响。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发表的数据，该数据描述了恒河猴TRIM5位点的功能多态性及其对SIV感染的影响。我们提出了三个特定目标，旨在1)充分评估trim5介导的抑制对慢病毒感染和疾病进展的影响（第一个特定目标）；2)确定ifn诱导的TRIM5基因表达是否被SIV感染特异性改变（second Specific Aim）；3)产生合理设计的HIV-1毒株，能够在恒河猴的原代细胞中稳健复制，代表所有常见的TRIM5基因型（third Specific Aim）。特异性Aim 1和特异性Aim 2将在生物相关的体内环境中更好地了解TRIM5，而特异性Aim 3的工作代表了在实际HIV-1感染动物模型方向上的关键但必要的一步。总之，这三个目标的工作将阐明TRIM5介导的抑制的生物学相关性，并导致改进艾滋病的动物模型。

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.