Creative and Novel Ideas in HIV Research (CNIHR) Program

The human genome is not a linear sequence, but rather a contorted knot of chromosomes in the three-dimensional space of the nucleus. The transcription community is now starting to realize that chromosomes do not work in isolation. Interchromosomal associations regulate gene expression. This innovation, however, has not been applied to retroviral infections. We still talk of host and pathogen genomes as if they only interact locally. I contend that these genomes are not only connected at a linear level, but also as an intertwined entity at the spatial level we refer to as a "hosthogen" genome. I hypothesize that long-range interactions between the human genome and HIV regulate transcription. My rationale for this contention is observation of similar bridges between the Epstein-Barr virus and human genomes. We will therefore use the associated chromatin trap assay followed by deep sequencing to identify two pieces of DNA, one from the host and one from the pathogen, that colocalize in a transcription-dependent manner. We will interpret differential colocalization as functional organization. This project will specifically address two questions: 1) Does HIV form bridges with repressed human genes? And 2) Are certain bridges specific to latent HIV? Components of conserved connected elements are likely to be functional regulators and worthwhile drug targets.