rigrag: high-resolution mapping of genic targeting preferences during HIV-1 integration in vitro and in vivo

Abstract HIV-1 integration favors recurrent integration gene (RIG) targets and genic proviruses can confer cell survival in vivo. However, the relationship between initial RIG integrants and how these evolve in patients over time are unknown. To address these shortcomings, we built phenomenological models of random integration in silico, which were used to identify 3718 RIGs as well as 2150 recurrent avoided genes from 1.7 million integration sites across 10 in vitro datasets. Despite RIGs comprising only 13% of human genes, they harbored 70% of genic HIV-1 integrations across in vitro and patient-derived datasets. Although previously reported to associate with super-enhancers, RIGs tracked more strongly with speckle-associated domains. While depletion of the integrase cofactor LEDGF/p75 significantly reduced recurrent HIV-1 integration in vitro, LEDGF/p75 primarily occupied non-speckle-associated regions of chromatin, suggesting a previously unappreciated dynamic aspect of LEDGF/p75 functionality in HIV-1 integration targeting. Finally, we identified only six genes from patient samples—BACH2, STAT5B, MKL1, MKL2, IL2RB and MDC1—that displayed enriched integration targeting frequencies and harbored proviruses that likely contributed to cell survival. Thus, despite the known preference of HIV-1 to target cancer-related genes for integration, we conclude that genic proviruses play a limited role to directly affect cell proliferation in vivo.