dCas9 Targeted Chromatin and Histone Enrichment for Mass Spectrometry (Catchet-MS) Identifies IKZF1 as a Novel Drug-Able Target for HIV-1 Latency Reversal

A major pharmacological strategy for HIV cure aims to reverse latency in infected cells to promote reservoir eradication. While the unbiased identification of putative molecular targets physically associated with the latent HIV-1 promoter would be crucial for the development of latency reversal drugs, 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 and identify the locus-bound protein complexes on the latent and activated HIV-1 promoter. Catchet-MS identified both known and novel host factors distinctly associated with the latent HIV-1 5’LTR. Among these, IKZF1 is a novel transcriptional repressor of HIV-1 required for latency. We find the drug iberdomide, which targets IKZF1 for degradation, to be a clinically advanced novel LRA that reverses latency in latent ex vivo HIV-1 infected primary CD4+ T cells and in cells isolated from virally suppressed HIV-1 infected participants.