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

Cellular chromatin is the first non-reversible contact point between incoming infectious agents, such as integrating viruses, and their host genomes. Retroviral integration depends on interactions between the viral intasome and host chromatin, involving interfaces between integrase, target DNA, and nucleosomal histones. While factors like LEDGF/p75 and chromatin compaction influence these interactions, the molecular mechanisms regulating access to nucleosomal interfaces remain unclear. In this study, we dissected how incoming intasomes engage nucleosome surfaces to facilitate integration. Using biochemical assays and molecular docking, we demonstrated that HIV-1 and PFV intasomes specifically bind distinct nucleosomal surfaces. Mapping these interactions onto trinucleosomes and simulating dynamic docking revealed that neighboring nucleosomes can mask functional interfaces, modulating HIV-1's ability to access its target. Conversely, PFV intasomes are less affected by chromatin compaction due to persistent accessibility of active nucleosomal sites. These findings provide the first structural insights into how chromatin architecture influences retroviral integration. Our results highlight divergent strategies by HIV-1 and PFV to engage chromatin, revealing how nucleosome properties govern the formation of active strand transfer complexes and emphasizing the evolution of virus-specific adaptation to chromatin landscapes.