Understanding the mechanisms underlying the non-random pattern of HIV integration within a host genomeremains an unsolved problem in biophysics. To address this issue, we formulate a generic multi-scale physical framework which models viral incorporation into DNA and chromosomes as stochastic "reconnections" between 3D-proximal polymer segments . Our model naturally predicts that successful integration events occur more often within more flexible or highly bent DNA, in agreement with long-standing observations. We further find that large-scale URLanisation biases integration events towards transcriptionally active genomic regions. We finally propose and solve a reaction-diffusion model which captures the observed distribution of HIV integration sites within the nuclear environment of T-cells. Our general framework can be used to predict HIV integration dynamics within different cell-lines or displaying different size, fraction of transcriptionally inactive genome and nuclear genomic arrangements .
The Human Immunodeficiency Virus (HIV) integrates its genetic material in a small and non-random fraction of all possible integration sites along the host genome. The mechanisms driving this non-uniform selection are not known. To address this issue, we formulate a generic physical model where we treat the viral incorporation into DNA and chromosomes as a stochastic quasi-equilibrium process . Our model rationalises a number of long-standing unexplained observations: we show that HIV integration is favoured in nucleosomal rather than naked DNA, and in flexible over rigid DNA. We find that these biases arise due to the difference in the bending energy barrier associated with DNA insertions. By coupling our model to a well-established framework for large-scale 3D URLanisation we discover that the non-random integration of HIV in human chromatin may be explained as due to large-scale accessibility of interphase chromosomes. Finally we propose and solve a reaction-diffusion model that recapitulates the distribution of HIV hot-spots within the nucleus of human T-cells. With few generic assumptions, our model can explain much of the current evidence on HIV integration and may be used to predict integration patterns in human cells .
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Understanding the mechanisms underlying the
The Human Immunodeficiency Virus (HIV) integrates its genetic material in a small and
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pattern of HIV integration within a host genomeremains an unsolved problem in biophysics.
fraction of all possible integration sites along the host genome. The mechanisms driving this non-uniform selection are not known.
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multi-scale physical framework which models
physical model where we treat the
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stochastic "reconnections" between 3D-proximal polymer segments
a stochastic quasi-equilibrium process
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naturally predicts that successful integration events occur more often within more flexible or highly bent DNA, in agreement with
rationalises a number of
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observations. We further find that
unexplained observations: we show that HIV integration is favoured in nucleosomal rather than naked DNA, and in flexible over rigid DNA. We find that these biases arise due to the difference in the bending energy barrier associated with DNA insertions. By coupling our model to a well-established framework for
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URLanisation biases integration events towards transcriptionally active genomic regions. We finally
3D URLanisation we discover that the non-random integration of HIV in human chromatin may be explained as due to large-scale accessibility of interphase chromosomes. Finally we
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which captures the observed
that recapitulates the
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integration sites within the nuclear environment of
hot-spots within the nucleus of human
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Our general framework can
With few generic assumptions, our model can explain much of the current evidence on HIV integration and may
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HIV integration dynamics within different cell-lines or displaying different size, fraction of transcriptionally inactive genome and nuclear genomic arrangements
integration patterns in human cells