PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency

Raquel Crespo, Enrico Ne, Julian Reinders, Jenny I.J. Meier, Chengcheng Li, Sanne Jansen, Alicja Górska, Selin Koçer, Tsung Wai Kan, Wouter Doff, Dick Dekkers, Jeroen Demmers, Robert Jan Palstra, Shringar Rao, Tokameh Mahmoudi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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Abstract

HIV-1 latency results from tightly regulated molecular processes that act at distinct steps of HIV-1 gene expression. Here, we characterize PCI domain-containing 2 (PCID2) protein, a subunit of the transcription and export complex 2 (TREX2) complex, to enforce transcriptional repression and post-transcriptional blocks to HIV-1 gene expression during latency. PCID2 bound the latent HIV-1 LTR (long terminal repeat) and repressed transcription initiation during latency. Depletion of PCID2 remodeled the chromatin landscape at the HIV-1 promoter and resulted in transcriptional activation and latency reversal. Immunoprecipitation coupled to mass spectrometry identified PCID2-interacting proteins to include negative viral RNA (vRNA) splicing regulators, and PCID2 depletion resulted in over-splicing of intron-containing vRNA in cell lines and primary cells obtained from PWH. MCM3AP and DSS1, two other RNA-binding TREX2 complex subunits, also inhibit transcription initiation and vRNA alternative splicing during latency. Thus, PCID2 is a novel HIV-1 latency-promoting factor, which in context of the TREX2 sub-complex PCID2-DSS1-MCM3AP blocks transcription and dysregulates vRNA processing.

Original languageEnglish
Article number109152
JournaliScience
Volume27
Issue number3
DOIs
Publication statusPublished - 15 Mar 2024

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Publisher Copyright: © 2024 The Author(s)

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