HIV silencing and cell survival signatures in infected T cell reservoirs

Iain C. Clark, Prakriti Mudvari, Shravan Thaploo, Samuel Smith, Mohammad Abu-Laban, Mehdi Hamouda, Marc Theberge, Sakshi Shah, Sung Hee Ko, Liliana Pérez, Daniel G. Bunis, James S. Lee, Divya Kilam, Saami Zakaria, Sally Choi, Samuel Darko, Amy R. Henry, Michael A. Wheeler, Rebecca Hoh, Salwan Butrus, Steven G. Deeks, Francisco J. Quintana, Daniel C. Douek, Adam R. Abate () and Eli A. Boritz ()
Additional contact information
Iain C. Clark: University of California, San Francisco
Prakriti Mudvari: National Institutes of Health
Shravan Thaploo: Brigham and Women’s Hospital, Harvard Medical School
Samuel Smith: National Institutes of Health
Mohammad Abu-Laban: National Institutes of Health
Mehdi Hamouda: National Institutes of Health
Marc Theberge: National Institutes of Health
Sakshi Shah: University of California, Berkeley
Sung Hee Ko: National Institutes of Health
Liliana Pérez: National Institutes of Health
Daniel G. Bunis: National Institutes of Health
James S. Lee: National Institutes of Health
Divya Kilam: National Institutes of Health
Saami Zakaria: National Institutes of Health
Sally Choi: National Institutes of Health
Samuel Darko: National Institutes of Health
Amy R. Henry: National Institutes of Health
Michael A. Wheeler: Brigham and Women’s Hospital, Harvard Medical School
Rebecca Hoh: University of California, San Francisco
Salwan Butrus: University of California, Berkeley
Steven G. Deeks: University of California, San Francisco
Francisco J. Quintana: Brigham and Women’s Hospital, Harvard Medical School
Daniel C. Douek: National Institutes of Health
Adam R. Abate: University of California, San Francisco
Eli A. Boritz: National Institutes of Health

Nature, 2023, vol. 614, issue 7947, 318-325

Abstract: Abstract Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure1–3, but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here we address this challenge using a microfluidic technology that isolates the transcriptomes of HIV-infected cells based solely on the detection of HIV DNA. HIV-DNA+ memory CD4 T cells in the blood from people receiving antiretroviral therapy showed inhibition of six transcriptomic pathways, including death receptor signalling, necroptosis signalling and antiproliferative Gα12/13 signalling. Moreover, two groups of genes identified by network co-expression analysis were significantly associated with HIV-DNA+ cells. These genes (n = 145) accounted for just 0.81% of the measured transcriptome and included negative regulators of HIV transcription that were higher in HIV-DNA+ cells, positive regulators of HIV transcription that were lower in HIV-DNA+ cells, and other genes involved in RNA processing, negative regulation of mRNA translation, and regulation of cell state and fate. These findings reveal that HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population with host gene expression patterns that favour HIV silencing, cell survival and cell proliferation, with important implications for the development of HIV cure strategies.

Date: 2023
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DOI: 10.1038/s41586-022-05556-6

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