Physical Principles of Retroviral Integration in the Human Genome

TL;DR

This paper introduces a biophysical model explaining retroviral DNA integration in the human genome, emphasizing the roles of DNA accessibility, elasticity, and chromatin state, aligning with experimental data and revealing physical factors influencing site selection.

Contribution

The study presents a novel biophysical framework modeling retroviral integration as polymer reconnections, highlighting physical effects and chromatin accessibility as key determinants of integration site preferences.

Findings

Integration favors nucleosomal and flexible DNA regions.

Physical effects like DNA elasticity influence integration biases.

Chromatin accessibility predominantly determines large-scale integration patterns.

Abstract

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.