HIV integrates into chromatin accessible areas of the host genome. The large diversity of the integration landscape suggests that there might be position effects controlling the fate of infection or “proviral fate” (decision-making between active or latent infection). Using both experimental and computational approaches our lab is interested in elucidating hidden regulatory programs (genetic/epigenetic features) that control proviral fate. A better understanding of these regulatory programs will help us devise strategies for personalized medicine approaches to cure patients from HIV infection.
At the molecular level, the dogma in the field poses that during latent infection, the HIV LTR promoter is in an “OFF state” due to RNA polymerase II (Pol II) pausing at the promoter as well as the presence of a restrictive host cell nucleosome barrier at the HIV genome. Conversely, during active infection, the HIV LTR promoter is in an “ON state” due to the action of cellular activators that promote Pol II pause release thereby leading to the synthesis of the viral-encoded activator Tat, which induces a robust positive feedback loop to sustain HIV transcription over time. However, how the HIV integration site in the host genome dictates proviral fate and what host cell factors control this process remain poorly understood. Unleashing the molecular rules controlling proviral fate will lead us not only to a better understanding of the basic biology of HIV but also will inform about novel factors and signaling pathways that could be exploited therapeutically.