Reversal of Epigenetic Silencing by the SMC5/6 Complex Rescues Integrase-Deficient HIV-1 Replication and Prevents the Establishment of a Latent Reservoir.

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2022

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Integration of HIV-1 DNA is an essential step in the viral life cycle, and how the unintegrated proviral DNA intermediate is transcriptionally silenced has been an ongoing question in the field. Here we show that this transcriptional silencing is epigenetic and demonstrate that the Tax transcription factor encoded by Human T-cell Leukemia Virus 1 (HTLV-1) can reverse the repressive epigenetic modifications on unintegrated, episomal HIV-1 circular DNA. Tax expression in HIV-1 mutants lacking functional integrase, and are normally transcriptionally silenced, causes the recruitment of NF-κB to unintegrated viral DNA promoter, reverses the repressive epigenetic modifications on the chromatinzed viral DNA, and leads to a robust, spreading infection. In addition, using an unbiased screen, we identify the host SMC5/6 complex as essential for epigenetically silencing unintegrated/ pre-integrated HIV-1 DNA. The SMC5/6 complex binds chromatinized HIV-1 DNA and triggers epigenetic silencing by inducing its SUMOylation through NSMCE2, an E3 SUMO ligase. Inhibiting this SUMOylation, by knocking out members of the SMC5/6 complex, mutationally disrupting its E3 ligase function, or by using a SUMOylation inhibitors like TAK-981 prevents this epigenetic silencing and rescues both viral gene transcription from, and replication of, integrase-deficient HIV-1. Finally, we show that inhibiting this initial SUMO-mediated silencing of HIV-1 DNA in integration-competent viruses with a functional integrase by the SMC5/6 complex drastically interferes with the establishment of latent HIV-1 infections in both CD4+ T cell lines and primary human T cells. We thus propose a new model to explain the establishment of the HIV-1 latent reservoir.

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Darryl irwan, Ishak (2022). Reversal of Epigenetic Silencing by the SMC5/6 Complex Rescues Integrase-Deficient HIV-1 Replication and Prevents the Establishment of a Latent Reservoir. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/26812.

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