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Physical Principles of Retroviral Integration in the Human Genome

By Davide Michieletto, Marina Lusic, D. Marenduzzo, Enzo Orlandini

Posted 12 Jan 2018
bioRxiv DOI: 10.1101/247437 (published DOI: 10.1038/s41467-019-08333-8)

Certain retroviruses, including HIV, insert their DNA in a non-random fraction of the host genome via poorly understood selection mechanisms. Here, we develop a biophysical model for retroviral integrations as stochastic and quasi-equilibrium topological reconnections between polymers. We discover that physical effects, such as DNA accessibility and elasticity, play important and universal roles in this process. Our simulations predict that integration is favoured within nucleosomal and flexible DNA, in line with experiments, and that these biases arise due to competing energy barriers associated with DNA deformations. By considering a long chromosomal region in human T-cells during interphase, we discover that at these larger scales integration sites are predominantly determined by chromatin accessibility. Finally, we propose and solve a reaction-diffusion problem that recapitulates the distribution of HIV hot-spots within T-cells. With few generic assumptions, our model can rationalise experimental observations and identifies previously unappreciated physical contributions to retroviral integration site selection.

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