Intrinsic Immunity and AIDS

描述(申请人提供)：TRIM5基因编码TRIM5a，一种对逆转录病毒感染具有内在抵抗力的胞浆蛋白。自从最初描述TRIM5a的抗逆转录病毒活性以来，已有100多篇相关出版物出现在主要的同行评议的艾滋病文献中。然而，这些研究几乎都集中在基于组织培养的检测中对TRIM5‘S抗病毒机制的结构/功能的研究。因此，令人惊讶的是，人们对体内TRIM5表达的调节、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研究小组发表的报告表明，在艾滋病的猕猴模型中，TRIM5的表达对SIV感染有显著影响。此外，恒河猴TRIM5基因的多态变异仍然是建立真正的HIV-1感染和疾病动物模型的巨大障碍。这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产生了具体的实际影响。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都是至关重要的。这项研究计划是基于我们实验室公布的描述恒河猴TRIM5基因座功能多态及其对SIV感染的影响的数据。我们提出了三个特定的目标，旨在1)全面评估TRIM5介导的抑制慢病毒感染和疾病进展的影响(第一个特定目标)；2)确定SIV感染是否特异性地改变了干扰素诱导的TRIM5基因的表达(第二个特定目标)；以及3)产生设计合理的能够在代表所有常见TRIM5基因的恒河猴原代细胞中复制的HIV-1毒株(第三个特定目标)。具体目标1和具体目标2将有助于在活体的生物学相关背景下更好地理解TRIM5，而具体目标3的工作是朝着艾滋病毒-1感染的实际动物模型方向迈出的关键但必要的一步。共同致力于这三个目标的工作将阐明TRIM5介导的抑制作用的生物学相关性，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.