dCas9 targeted chromatin and histone enrichmentfor mass spectrometry (Catchet-MS) identifies IKZF1as a novel drug-able target for HIV-1 latency reversal

A major pharmacological strategy toward HIV cure aims to reverse latency in infected cells as a first step leading to their elimination. While the unbiased identification of molecular targets physically associated with the latent HIV-1 provirus would be highly valuable to unravel the molecular correlates of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has not been possible. Here we use dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to isolate the latent and activated HIV-1 5LTR, followed by MS identification of the differentially locus-bound proteins. Catchet-MS identified known and novel latent 5LTR-associated host factors. Among these, IKZF1 is a novel HIV-1 transcriptional repressor, required for Polycomb Repressive Complex 2 recruitment to the LTR. We find the drug iberdomide, which targets IKZF1 for degradation, to be a clinically advanced novel LRA that reverses HIV-1 latency in CD4+T-cells isolated from virally suppressed HIV-1 infected participants.