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HIV silencing and cell survival signatures in infected T cell reservoirs

Authors
  • Clark, Iain C
  • Mudvari, Prakriti
  • Thaploo, Shravan
  • Smith, Samuel
  • Abu-Laban, Mohammad
  • Hamouda, Mehdi
  • Theberge, Marc
  • Shah, Sakshi
  • Ko, Sung Hee
  • Pérez, Liliana
  • Bunis, Daniel G
  • Lee, James S
  • Kilam, Divya
  • Zakaria, Saami
  • Choi, Sally
  • Darko, Samuel
  • Henry, Amy R
  • Wheeler, Michael A
  • Hoh, Rebecca
  • Butrus, Salwan
  • And 5 more
Publication Date
Feb 09, 2023
Source
eScholarship - University of California
Keywords
License
Unknown
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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.

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