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Single-cell immune profiling reveals the impact of antiretroviral therapy on HIV-1-induced immune dysfunction, T cell clonal expansion, and HIV-1 persistence in vivo

Jack A. Collora, Delia Pinto-Santini, Siavash Pasalar, Neal Ravindra, Carmela Ganoza, Javier Lama, Ricardo Alfaro, Jennifer Chiarella, Serena Spudich, David van Dijk, Ann Duerr, Ya-Chi Ho
doi: https://doi.org/10.1101/2021.01.27.428491
Jack A. Collora
1Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06519, USA
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Delia Pinto-Santini
2Vaccine and Infectious Disease & Public Health Science Divisions, Fred Hutchinson Cancer Research Center, Seattle, MA, 98109, USA
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Siavash Pasalar
2Vaccine and Infectious Disease & Public Health Science Divisions, Fred Hutchinson Cancer Research Center, Seattle, MA, 98109, USA
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Neal Ravindra
3Department of Internal Medicine (Cardiology), Yale School of Medicine, New Haven, CT 06520, USA
4Department of Computer Science, Yale University, New Haven, CT 06520, USA
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Carmela Ganoza
5Asociación Civil Impacta Salud y Educación, Lima, 15063, Perú
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Javier Lama
5Asociación Civil Impacta Salud y Educación, Lima, 15063, Perú
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Ricardo Alfaro
6Centro de Investigaciones Tecnológicas Biomédicas y Medioambientales (CITBM), Lima, 07006, Perú
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Jennifer Chiarella
7Department of Neurology, Yale University School of Medicine, New Haven, CT 06519, USA
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Serena Spudich
7Department of Neurology, Yale University School of Medicine, New Haven, CT 06519, USA
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David van Dijk
3Department of Internal Medicine (Cardiology), Yale School of Medicine, New Haven, CT 06520, USA
4Department of Computer Science, Yale University, New Haven, CT 06520, USA
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Ann Duerr
2Vaccine and Infectious Disease & Public Health Science Divisions, Fred Hutchinson Cancer Research Center, Seattle, MA, 98109, USA
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Ya-Chi Ho
1Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06519, USA
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  • For correspondence: ya-chi.ho@yale.edu
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Abstract

Despite antiretroviral therapy (ART), HIV-1 persists in proliferating T cell clones that increase over time. To understand whether early ART affects HIV-1 persistence in vivo, we performed single-cell ECCITE-seq and profiled 89,279 CD4+ T cells in paired samples during viremia and after immediate versus delayed ART in six people in the randomized interventional Sabes study. We found that immediate ART partially reverted TNF responses while delayed ART did not. Antigen and TNF responses persisted despite immediate ART and shaped the transcriptional landscape of CD4+ T cells, HIV-1 RNA+ cells, and T cell clones harboring them (cloneHIV-1). Some HIV-1 RNA+ cells reside in the most clonally expanded cytotoxic T cell populations (GZMB and GZMK Th1 cells). CloneHIV-1+ were larger in clone size, persisted despite ART, and exhibited transcriptional signatures of antigen, cytotoxic effector, and cytokine responses. Using machine-learning algorithms, we identified markers for HIV-1 RNA+ cells and cloneHIV-1+ as potential therapeutic targets. Overall, by combining single-cell immune profiling and T cell expansion dynamics tracking, we identified drivers of HIV-1 persistence in vivo.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 28, 2021.
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Single-cell immune profiling reveals the impact of antiretroviral therapy on HIV-1-induced immune dysfunction, T cell clonal expansion, and HIV-1 persistence in vivo
Jack A. Collora, Delia Pinto-Santini, Siavash Pasalar, Neal Ravindra, Carmela Ganoza, Javier Lama, Ricardo Alfaro, Jennifer Chiarella, Serena Spudich, David van Dijk, Ann Duerr, Ya-Chi Ho
bioRxiv 2021.01.27.428491; doi: https://doi.org/10.1101/2021.01.27.428491
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Single-cell immune profiling reveals the impact of antiretroviral therapy on HIV-1-induced immune dysfunction, T cell clonal expansion, and HIV-1 persistence in vivo
Jack A. Collora, Delia Pinto-Santini, Siavash Pasalar, Neal Ravindra, Carmela Ganoza, Javier Lama, Ricardo Alfaro, Jennifer Chiarella, Serena Spudich, David van Dijk, Ann Duerr, Ya-Chi Ho
bioRxiv 2021.01.27.428491; doi: https://doi.org/10.1101/2021.01.27.428491

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