Single-cell epigenetic, transcriptional, and protein profiling of latent and active HIV-1 reservoir revealed that IKZF3 promotes HIV-1 persistence

Understanding how HIV-1-infected cells proliferate and persist is key to HIV-1 eradication, but the heterogeneity and rarity of HIV-1-infected cells hamper mechanistic interrogations. Here, we used single-cell DOGMA-seq to simultaneously capture transcription factor accessibility, transcriptome, sur...

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Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Vol. 56; no. 11; pp. 2584 - 2601.e7
Main Authors:	Wei, Yulong, Davenport, Timothy C, Collora, Jack A, Ma, Haocong Katherine, Pinto-Santini, Delia, Lama, Javier, Alfaro, Ricardo, Duerr, Ann, Ho, Ya-Chi
Format:	Journal Article
Language:	English
Published:	United States 14-11-2023
Subjects:	CD4-Positive T-Lymphocytes Epigenesis, Genetic HIV Infections - genetics HIV-1 - physiology Humans Ikaros Transcription Factor - genetics Transcription Factor AP-1 Virus Latency - genetics transcription factor acute viral infection single-cell ATAC-seq T cell differentiation HIV persistence single-cell RNA-seq HIV latent reservoir memory CD4(+) T cells HIV cure IKZF3 Aiolos
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Summary:	Understanding how HIV-1-infected cells proliferate and persist is key to HIV-1 eradication, but the heterogeneity and rarity of HIV-1-infected cells hamper mechanistic interrogations. Here, we used single-cell DOGMA-seq to simultaneously capture transcription factor accessibility, transcriptome, surface proteins, HIV-1 DNA, and HIV-1 RNA in memory CD4 T cells from six people living with HIV-1 during viremia and after suppressive antiretroviral therapy. We identified increased transcription factor accessibility in latent HIV-1-infected cells (RORC) and transcriptionally active HIV-1-infected cells (interferon regulatory transcription factor [IRF] and activator protein 1 [AP-1]). A proliferation program (IKZF3, IL21, BIRC5, and MKI67 co-expression) promoted the survival of transcriptionally active HIV-1-infected cells. Both latent and transcriptionally active HIV-1-infected cells had increased IKZF3 (Aiolos) expression. Distinct epigenetic programs drove the heterogeneous cellular states of HIV-1-infected cells: IRF:activation, Eomes:cytotoxic effector differentiation, AP-1:migration, and cell death. Our study revealed the single-cell epigenetic, transcriptional, and protein states of latent and transcriptionally active HIV-1-infected cells and cellular programs promoting HIV-1 persistence.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Y.W., J.A.C., and Y.-C.H. designed and performed DOGMA-seq experiments. Y.W. performed bioinformatic analyses. T.C.D. performed flow cytometry with help from K.H.M and Y.-C.H. D.P.-S., J.L., R.A., and A.C.D. recruited study participants and processed clinical samples. A.C.D. designed the Sabes and MERLIN studies and assumed oversight for study conduct and analysis. Y.W. and Y.C.-H. wrote the manuscript with input from all authors.
ISSN:	1074-7613 1097-4180 1097-4180
DOI:	10.1016/j.immuni.2023.10.002