Physical Principles of Retroviral integration in the human genome

Certain retroviruses, including HIV, insert their DNA in a small and non-random fraction of the host genome. This selection happens via poorly understood mechanisms and it strongly affects the ability of retroviruses to replicate and infect the host. Traditionally, this lack of randomness is attributed to molecular factors and protein chaperones. In spite of this, decades of research have not managed to produce unambiguous evidence for which molecules or proteins may guide this integration site selection.
To shed light into this issue we developed a biophysical model for retroviral integration as stochastic and quasi-equilibrium topological reconnections between polymers [1]. Our simulations reveal that physical effects, such as DNA accessibility and elasticity, play important and universal roles in the integration site selection. For instance, our simulations predict that integration is favoured within nucleosomal and flexible DNA, thus rationalizing decades of in vitro experiments [2].
By considering a long chromosomal region in human T-cells during interphase, we are also able to compare our predictions against real data from parallel sequencing of the genome of HIV infected cells [3] and 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 the whole nucleus of T-cells [4].
With few generic assumptions, our model can rationalise experimental observations and identifies previously unappreciated physical contributions to retroviral integration site selection.

[1] D. Michieletto, M. Lusic, D. Marenduzzo, and E. Orlandini, “Physical principles of retroviral integration in the human genome,” Nature Communications, 10(1), 575, 2019. [2] D. Pruss, F. Bushman, and A. Wolffe, “Human immunodeficiency virus integrase directs integration to sites of severe DNA distortion within the nucleosome core,” Proc. Natl. Acad. Sci. USA, 91, 5913–5917, 1994. [3] G. P. Wang, et al., “HIV integration site selection : Analysis by massively parallel pyrosequencing reveals association with epigenetic modifications,” Genome Res., 17, 1186–1194, 2007. [4] B. Marini et al., “Nuclear architecture dictates HIV-1 integration site selection,” Nature, 521(7551), 227, 2015.

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