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Despite significant advances in our understanding of HIV, a cure has not been realized for the more than 34 million infected with this virus. HIV is incurable because infected individuals harbor cells where the HIV provirus is integrated into the host's DNA but is not actively replicating and thus is not inhibited by antiviral drugs. Similarly, these latently infected cells are not detected by the immune system. Intermittently, these latently infected cells produce a burst of virus before retreating back into latency. These small bursts of virus contribute both to the low viral load detected in treated subjects and to rapid reseeding of HIV infection following ART withdrawal. We show that miR-155 helps reestablish viral latency by interfering with the HIV-activating effects of TRIM32. TRIM32, an E3 ubiquitin ligase, activates the HIV LTR by an unexpected mechanism involving direct ubiquitination of IkappaBalpha; leading to NF-kappaB nuclear translocation and engagement of the duplicated kappaB enhancers within the LTR. These findings highlight a latency-promoting role for one cellular miRNA that acts by suppressing an HIV activator. Understanding the precise mechanisms governing HIV latency will be pivotal for development of a safe, effective, and scalable HIV cure.

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