Citations 2
CPSF6-Dependent Targeting of Speckle-Associated Domains Distinguishes Primate from Nonprimate Lentiviral Integration
Li, Wen , Sowd, Gregory A. , Bedwell, Gregory J. , Jang, Sooin , Achuthan, Vasudevan, Oleru, Amarachi V., Wong, Doris , Fadel, Hind J., KewalRamani, Vineet N. , Poeschla, Eric M. , Herschhorn, Alon , Engelman, Alan , Singh, Parmit Kumar , Wong, Doris, Lee, Kyeongeun
mBio | September 28, 2020 | Volume: 11 | Issue: 5 | Pages: No page available
Integration is the defining step of the retroviral life cycle and underlies the inability to cure HIV/AIDS through the use of intensified antiviral therapy. The reservoir of latent, replication-competent proviruses that forms early during HIV infection reseeds viremia when patients discontinue medication. HIV cure research is accordingly focused on the factors that guide provirus formation and associated chromatin environments that regulate transcriptional reactivation, and studies of orthologous infectious agents such as nonprimate lentiviruses can inform basic principles of HIV biology. HIV-1 utilizes the integrase-binding protein LEDGF/p75 and the capsid interactor CPSF6 to target speckle-associated domains (SPADs) for integration. However, the extent to which these two host proteins regulate integration of other lentiviruses is largely unknown. Here, we mapped millions of retroviral integration sites in cell lines that were depleted for LEDGF/p75 and/or CPSF6. Our results reveal that primate lentiviruses uniquely target SPADs for integration in a CPSF6-dependent manner.
A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin
Sowd, Gregory A. , Serrao, Erik , Wang, Hao , Fadel, Hind J., Poeschla, Eric M. , Engelman, Alan , Wang, Weifeng
Proceedings of the National Academy of Sciences | February 9, 2016 | Volume: 113 | Issue: 8 | Pages: No page available
Significance HIV-1 requires integration for efficient gene expression, and the local chromatin environment significantly influences the level of HIV-1 transcription. Silent, integrated proviruses constitute the latent HIV reservoir. As HIV-1 commandeers cellular factors to dictate its preferred integration sites, these interactions consequentially influence latency. We examined the impact of polyadenylation specificity factor CPSF6, which binds HIV-1 capsid, and the integrase-binding chromatin reader LEDGF/p75 on viral infection and integration site distribution. Integration sites were determined in cells knocked down or knocked out for one or both host factors. Our data indicate that CPSF6 directs HIV-1 to transcriptionally active chromatin, where LEDGF/p75 predominantly directs the positions of integration within genes. These findings clarify the roles of cellular forces that dictate HIV-1 integration preferences and hence virus pathogenesis.