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bioRxiv · 10.1101/2025.05.05.652197

Molecular basis for the regulation of retroviral nucleosomal integration by chromatin compaction

Zgadzayy, Y.·Martins, F. G.·Bertinetti, C.·Autin, M.·Batisse, J.·Tumiotto, C.·Paul, L.·Ruff, M.·Sousa, S.·Parissi, V.
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Abstract

Cellular chromatin represents the first nonreversible contact point between the genomes of incoming infectious agents, such as integrative viruses, and their hosts. The integration of retroviral genomes requires a functional association between the viral integration complex (intasome) and host chromatin, mediated through multiple interfaces between the integrase, target DNA, and histone components of the nucleosome. Previous studies have shown that these associations are regulated by cellular factors, such as LEDGF/p75 for lentiviruses, and by the degree of compaction of the chromatin surrounding the insertion site. However, the molecular mechanisms underlying the regulation of access to local nucleosomal functional interfaces remain elusive. In this study, we dissected how incoming intasomes engage nucleosome surface to achieve efficient integration. Combining biochemical approaches with molecular docking analysis, we demonstrated that HIV-1 and PFV intasomes distinctly and specifically interact with nucleosome surfaces. Mapping these interfaces onto a compacted trinucleosomal structure and simulating the dynamic docking of the intasome at these sites revealed how neighboring nucleosomes modulate the functional binding of the HIV-1 intasome to the catalytic target nucleosome by masking these functional interfaces. In contrast, the lower susceptibility of the PFV intasome to chromatin compaction was due to the persisting accessibility of active nucleosomal interfaces. Together, these data provide the first molecular and structural insights into how chromatin compaction influence retroviral integration. Our results especially show how nucleosome-intasomes docking sites participate in modulating the sensitivity of the retroviral integration to chromatin structure. Overall, our data reveal that HIV-1 and PFV integration rely on nucleosomes with distinct structural and functional properties at the insertion site to form an active strand transfer complex. This work further demonstrated that retroviruses have evolved distinct strategies to engage suitable chromatin structures for efficient integration highlighting a divergence in retroviral adaptation mechanisms.

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Zgadzayy, Y., Martins, F. G., Bertinetti, C., Autin, M., Batisse, J., Tumiotto, C., Paul, L., Ruff, M., Sousa, S., Parissi, V.. 2025-05-07. Molecular basis for the regulation of retroviral nucleosomal integration by chromatin compaction. https://doi.org/10.1101/2025.05.05.652197

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