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Peer-reviewedCC BYScience Advances

Cell heterogeneity contributes to the variable response of HIV-1 to latency-reversing agents

  • Rachel Topno1,2
  • Hussein Karaki1,3
  • Flavia Mazzarda1
  • Oriane Pourcelot1
  • Manon Philippe1
  • Kazem Zibara3
  • Ovidiu Radulescu2
  • Edouard Bertrand1
  1. 1IGH, University of Montpellier and CNRS, 141 Rue de la Cardonille, Montpellier 34094, France.
  2. 2LPHI, University of Montpellier, CNRS and INSERM, Place Eugene Bataillon, Montpellier 34095, France.
  3. 3Research and Analysis Platform in Environmental Sciences (EDST-PRASE), Lebanese University, Hadath P.O. Box 14-6573, Lebanon.
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Abstract

Transcriptional noise contributes to gene expression variability, but its origin and impact in HIV-1 latency remain incompletely characterized. Here, we combine a dual-copy MS2-tagging system with dedicated mathematical analysis to investigate the variability of HIV-1 transcription in live cells. In the basal state, the transcriptional activity of proviruses located in the same cell was uncorrelated, indicating that expression variability primarily comes from the intrinsic stochasticity of promoter dynamics. Upon stimulation with diverse latency-reversing agents, transcription of viral copies became more correlated within cells than across them, revealing a shift from promoter-driven to cell state-driven variability. Analysis of the molecular drug targets confirmed variable effects across cells. Our findings indicate that cellular heterogeneity can shape the response to latency-reversing agents and demonstrate how quantitative tools can dissect noise sources. This work offers mechanistic insights into HIV-1 latency and informs strategies to target the latent viral reservoir.

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Cite

BibTeXRIS
BibTeX
@article{topno2026cell,
  title = {{Cell heterogeneity contributes to the variable response of HIV-1 to latency-reversing agents}},
  author = {Rachel Topno and Hussein Karaki and Flavia Mazzarda and Oriane Pourcelot and Manon Philippe and Kazem Zibara and Ovidiu Radulescu and Edouard Bertrand},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeb1435},
  url = {https://www.science.org/doi/10.1126/sciadv.aeb1435},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cell heterogeneity contributes to the variable response of HIV-1 to latency-reversing agents
AU  - Rachel Topno
AU  - Hussein Karaki
AU  - Flavia Mazzarda
AU  - Oriane Pourcelot
AU  - Manon Philippe
AU  - Kazem Zibara
AU  - Ovidiu Radulescu
AU  - Edouard Bertrand
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aeb1435
UR  - https://www.science.org/doi/10.1126/sciadv.aeb1435
AB  - Transcriptional noise contributes to gene expression variability, but its origin and impact in HIV-1 latency remain incompletely characterized. Here, we combine a dual-copy MS2-tagging system with dedicated mathematical analysis to investigate the variability of HIV-1 transcription in live cells. In the basal state, the transcriptional activity of proviruses located in the same cell was uncorrelated, indicating that expression variability primarily comes from the intrinsic stochasticity of promoter dynamics. Upon stimulation with diverse latency-reversing agents, transcription of viral copies became more correlated within cells than across them, revealing a shift from promoter-driven to cell state-driven variability. Analysis of the molecular drug targets confirmed variable effects across cells. Our findings indicate that cellular heterogeneity can shape the response to latency-reversing agents and demonstrate how quantitative tools can dissect noise sources. This work offers mechanistic insights into HIV-1 latency and informs strategies to target the latent viral reservoir.
SN  - 2375-2548
ER  -