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. 2021 Mar 18;12:636642. doi: 10.3389/fmicb.2021.636642

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Copyright © 2021 Janssens, Bruggemans, Christ and Debyser.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Determinants of HIV-1 integration site selection. The HIV-1 nuclear import pathway is linked to integration. The HIV-1 PIC engages NUPs, favoring integration in close proximity to the NPC (upper left part). Second, cellular cofactors affect the proviral integration site. LEDGF/p75 interacts with HIV-1 IN and targets integration toward active genes. The HIV-1 PIC interacts with other cellular cofactors that affect integration: TRN-SR2 and CPSF6 have been associated with integration in gene-dense regions. TRN-SR2 mediates nuclear import of SR proteins, such as CPSF6, and interacts with the viral IN. The exact mechanism by which these proteins affect nuclear import and integration is not completely understood yet (upper right part). Third, the nuclear architecture affects integration site selection. The heterochromatin condensed regions in the LADs are disfavored, while gene-rich and euchromatin regions in close association with the NPC are frequently targeted by HIV-1 (lower part). PIC, pre-integration complex; NUPs, nucleoporins; LEDGF/p75, lens-epithelium-derived growth factor; IN, integrase; TRN-SR2, transportin-SR2; CPSF6, cleavage and polyadenylation specificity factor 6; LAD, lamina-associated domains; figure created with BioRender.com.