The persistence of a latent reservoir containing transcriptionally silent, but replication-competent, integrated provirus is a serious challenge to HIV eradication. HIV integration is under the control of LEDGF/p75, the cellular cofactor of viral integrase. Investigating possible postintegration roles for LEDGF/p75, we find that LEDGF/p75 represses HIV expression in latently infected cells. LEDGF/p75 associated with two proteins involved in the control of gene expression and chromatin structure, Spt6 and Iws1, to form a stable complex. Iws1 plays a role in the establishment of latent infection, whereas Spt6 functions to recruit Iws1 and LEDGF/p75 to the silenced provirus and maintains histone occupancy at the HIV promoter. In latently infected cells, depletion of the complex results in reactivation of HIV expression Altogether, our results indicate that a complex containing LEDGF/p75, Iws1, and Spt6 participates in regulating postintegration steps of HIV latency.

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