Do antibodies to HIV-Tat regulate redox status in HIV?

描述(申请人提供)：虽然HIV-Tat是众所周知的HIV转录的细胞内调节器，但它也被证明通过无前导路径分泌到循环中。分泌的TAT已被证明可以加剧感染细胞中的艾滋病毒复制，并在未感染的细胞和动物中诱导氧化应激。有证据表明，TAT、氧化应激和HIV疾病进展之间存在有趣的联系，证据表明：1)无进展者往往具有高滴度的抗TAT抗体，这些抗体可能起到清除或中和分泌的TAT的作用。2)氧化应激提示HIV病预后不良。3)TAT参与了氧化应激的诱导。然而，人们对这些抗体的性质和特异性以及它们与HIV-1感染中氧化应激发生(或预防)的关系知之甚少。这里的研究解决了这个问题。我们建议使用高度敏感的蛋白质组学工具来检测来自HIV感染人群的储存血清，我们已经广泛地表征了该人群的氧化还原状态以及HIV疾病的细胞和其他标志。使用这些工具，我们将量化血清TAT蛋白和抗TAT抗体的水平。此外，通过扩大TAT微阵列靶标的范围，包括一系列重叠的TAT多肽和突变的TAT蛋白，我们将表征单个血清中抗TAT抗体特异性的精细特异性。因此，我们建议确定某些抗体或针对TAT分子特定区域的抗体模式(特异性图谱)是否与疾病状态有关。最后，由于我们用来检测抗TAT抗体的微阵列可以同时检测对广泛的碳水化合物和蛋白质抗原的抗体，我们建议确定抗体对自身或外来抗原的反应模式是否与氧化还原或疾病状态有关。总之，这些研究将有助于了解艾滋病毒感染中氧化应激的来源(S)，并确定预测艾滋病毒疾病进展的潜在标记物。

DESCRIPTION (provided by applicant): Although HIV-Tat is well known as an intracellular regulator of HIV transcription, it has also been shown to be secreted into circulation via a leader-less pathway. The secreted tat has been shown to exacerbate HIV replication in infected cells and to induce oxidative stress in uninfected cells and animals. Intriguing connections among tat, oxidative stress and HIV disease progression are suggested by evidence showing 1) that non-progressors tend to have high titers of anti-tat antibodies that presumably act to remove or neutralize secreted tat. 2) that oxidative stress indicates poor prognosis of HIV disease. 3) that Tat is involved in the induction of oxidative stress. However, little is known about the nature and specificity of these antibodies and their relationship if any to the occurrence (or prevention) of oxidative stress in HIV-1 infection. Studies here address this issue. We propose to use the highly sensitive proteomic tools to examine stored sera from an HIV-infected population that we have extensively characterized for redox status and cellular and other markers of HIV disease. With these tools, we will quantitate serum levels of Tat protein and anti-Tat antibodies. In addition, by extending the range of tat microarray targets to include a full panel of overlapping Tat peptides and mutant Tat proteins, we will characterize the fine specificities of anti-tat antibody specificities in individual sera. Thus, we propose to determine whether certain antibodies or patterns of antibodies to particular regions of the Tat molecule (specificity profiles) are associated with disease status. Finally, because the microarrays that we use to detect anti-Tat antibodies can concomitantly detect antibodies to a broad array of carbohydrate and protein antigens, we propose to determine whether patterns of antibody reactivity to self or foreign antigens are associated with redox or disease status. Collectively, these studies will contribute to understanding the source(s) of oxidative stress in HIV infection and to identifying potential markers for predicting HIV disease progression.