Catchet-MS identifies IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents

Enrico Ne, Raquel Crespo, Ray Izquierdo-Lara, Shringar Rao, Selin Koçer, Alicja Górska, Thomas Van Staveren, Tsung Wai Kan, David Van De Vijver, Dick Dekkers, Casper Rokx, Panagiotis Moulos, Pantelis Hatzis, Robert Jan Palstra, Jeroen Demmers, Tokameh Mahmoudi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

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 determinants of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has been challenging. Here we use a dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to probe the differential protein composition of the latent and activated HIV-1 5′LTR. Catchet-MS identified known and novel latent 5′LTR-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 clinically advanced thalidomide analogue iberdomide, and the FDA approved analogues lenalidomide and pomalidomide, to be novel LRAs. We demonstrate that, by targeting IKZF1 for degradation, these compounds reverse HIV-1 latency in CD4+ T-cells isolated from virally suppressed people living with HIV-1 and that they are able to synergize with other known LRAs.

Original languageEnglish
Pages (from-to)5577-5598
Number of pages22
JournalNucleic Acids Research
Volume50
Issue number10
DOIs
Publication statusPublished - 10 Jun 2022

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