We have generated a global map of Tat binding to the human genome. Surprisingly, the majority of Tat target regions lie within DNA repeat elements. In fact, over 30% of all Tat target regions are located at or near Alu elements. Interestingly, Tat increases the transcription of Alu repeat elements by increasing the activity of cellular transcription factor TFIIIC in Jurkat cells 
. Since Alu elements antagonize the interferon-induced protein kinase R (PKR) activation 
and PKR is known to repress protein synthesis when cells are under stress, Tat binding at Alu elements may be important to enable efficient viral replication in the host cell. In addition, these Alu elements may affect regulation of genes with functions related to HIV-1 biology.
In relation to gene regulation, Tat binding sites are distal to genes with functions in T cell biology as determined by knockout models in mice. These data suggest that Tat may exert its effects on its target genes through distant regulatory elements. If so, then Tat binding, in and of itself, may highlight previously unknown cis-regulatory elements within the genome. We did not find a significant correlation between Tat binding and gene expression. The effects of Tat on gene expression may be too subtle for the microarrays to detect. Alternatively, Tat may affect the regulation of its target genes through effects on mRNA structure that is not evident by expression analysis.
We found only a few genes with Tat binding to the vicinity of their TSS. This is partly due to the stringent cutoff used in this study to maintain a False Discovery Rate (FDR) under 5%. For instance, gene promoters previously shown to be bound by Tat binding such as IL-6 
and ß2 microglobulin 
, showed some Tat binding above background but did not pass our criteria for statistical significance. Also, previous studies used different cell culture systems to determine Tat binding in vivo. These differences may also lead to identification of different sets of target genes.
Since Tat is not known to bind DNA directly, the mechanism by which Tat binds to specific regions of the genome may partly involve interactions with host cellular factors. By comparing our Tat binding data to the published datasets in Jurkat cells, we found that Tat binds to gene promoters that were bound by ETS1 and CBP, but not with RUNX1, in non-Tat expressing Jurkat cells. A similar positive relationship was found between Tat binding and two histone methylation marks, H3K4me3 and H3K27me3. These data raise the possibility that Tat may distinguish its target regions through specific host transcription co-factors or chromatin marks. However, our data does not include or exclude ETS1, CBP or the histone modifications as the mediators of Tat recruitment. Binding analyses of specific Tat mutants that disrupt its interaction with specific cellular factors are required to determine potential mechanisms of Tat recruitment. It is also possible that Tat binds to the genome through an RNA component. Nonetheless, our results demonstrate that in addition to known roles for Tat in enhancing elongation of viral transcription, Tat also binds to the host genome at specific genomic locations with potentially important consequences for the viral life cycle.