FUSED IN SARCOMA ASSOCIATES WITH THE SUPER ELONGATION COMPLEX AND RESTRICTS HIV TRANSCRIPTION

Despite the success of anti-retroviral therapy in reducing viral load, Human Immunodeficiency Virus (HIV) still persists and resides in a long-lived infected cell reservoir that harbors latent proviruses. Among the various mechanisms that maintain HIV in a latency state, transcription repression of the host transcription machinery is considered a key driving force. For efficient gene transcription, HIV is heavily dependent on the function of the viral Tat protein that tethers the Super Elongation Complex (SEC) and Positive Transcription Elongation Factor b (P-TEFb) to the viral promoter. SEC and P-TEFb join forces to release RNA Polymerase II (RNAPII) from its promoter-proximal pausing sites. However, despite the advance in understanding the parameters that establish HIV latency, the role of SEC in modulating this step is less defined, as the molecular mechanisms that regulate its functions remain elusive.


In this study, we set to identify novel SEC host partners that potentially regulate its activity and modulate HIV latency. We find that Fused in Sarcoma - FUS, associates with the AFF4 - AF4/FMR2 family member 4 -AFF4, subunit of SEC, and restricts HIV gene transcription. FUS is also recruited to the viral promoter and modulates the promoter occupancy of SEC and P-TEFb. Biochemical analysis confirms that in cells, FUS associates with RNAPII and P-TEFb, while in-vitro, C- terminal residues of AFF4 mediate interactions with FUS. Significantly, depletion of FUS expression activates HIV from its latent state. As HIV serves as a model for studying eukaryotic gene regulation, Chip-Seq analysis demonstrates that FUS occupies Transcription Starting Sites (TSS) genome-wide. We conclude that through SEC, FUS associates with the transcription elongation complex and restricts HIV transcription elongation to modulate viral latency.