Abstract
BackgroundStable insertion of the retroviral DNA genome into host chromatin requires the functional association between the intasome (integrase·viral DNA complex) and the nucleosome. The data from the literature suggest that direct protein–protein contacts between integrase and histones may be involved in anchoring the intasome to the nucleosome. Since histone tails are candidates for interactions with the incoming intasomes we have investigated whether they could participate in modulating the nucleosomal integration process.ResultsWe show here that histone tails are required for an optimal association between HIV-1 integrase (IN) and the nucleosome for efficient integration. We also demonstrate direct interactions between IN and the amino-terminal tail of human histone H4 in vitro. Structure/function studies enabled us to identify amino acids in the carboxy-terminal domain of IN that are important for this interaction. Analysis of the nucleosome-binding properties of catalytically active mutated INs confirmed that their ability to engage the nucleosome for integration in vitro was affected. Pseudovirus particles bearing mutations that affect the IN/H4 association also showed impaired replication capacity due to altered integration and re-targeting of their insertion sites toward dynamic regions of the chromatin with lower nucleosome occupancy.ConclusionsCollectively, our data support a functional association between HIV-1 IN and histone tails that promotes anchoring of the intasome to nucleosomes and optimal integration into chromatin.
Highlights
Stable insertion of the retroviral DNA genome into host chromatin requires the functional association between the intasome and the nucleosome
We have recently reported that local nucleosome dissociation by the FACT histone chaperon generates chromatin structures favoring HIV-1 integration both in vitro and in cells [9]
Taken together these data suggest that additional contacts between the HIV-1 intasome and the nucleosome, which may be prevented during compaction and made accessible during chromatin remodeling, could be required for efficient integration
Summary
Stable insertion of the retroviral DNA genome into host chromatin requires the functional association between the intasome (integrase·viral DNA complex) and the nucleosome. Integration occurs in strongly preferred regions of the genome that depend on the Benleulmi et al Retrovirology (2017) 14:54 a suitable chromatin region via the association between IN and cellular factors, followed by local insertion step requiring IN-nucleosome interaction This final association between IN and its nucleosomal target substrate is a process governed by the intasome and nucleosomal DNA constraints and regulated by nucleosome density and remodeling activities [5,6,7,8]. We have recently reported that local nucleosome dissociation by the FACT histone chaperon generates chromatin structures favoring HIV-1 integration both in vitro and in cells [9] Taken together these data suggest that additional contacts between the HIV-1 intasome and the nucleosome, which may be prevented during compaction and made accessible during chromatin remodeling, could be required for efficient integration. Due to the lack of information regarding the mechanisms of nucleosome capture by the HIV-1 intasome, we investigated the potential role of IN/ histone interactions in regulating HIV-1 integration
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