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. ? ?
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