Defective proviruses cause T cell reprogramming through promoter exaptation in HIV-1 infection

Hamann, M. V.; Brauckmann, L.; Schwarz, C.; Spohn, M.; Stoeck, R.; Leddy, S.; Frouard, J.; Adiba, M.; Thiele, F.; Virdi, S.; Grundhoff, A.; Feschotte, C.; Roan, N. R.; Tolosa, E.; Lange, U. C.

doi:10.1101/2025.09.22.676989

bioRxiv · 10.1101/2025.09.22.676989

Defective proviruses cause T cell reprogramming through promoter exaptation in HIV-1 infection

Hamann, M. V.·Brauckmann, L.·Schwarz, C.·Spohn, M.·Stoeck, R.·Leddy, S.·Frouard, J.·Adiba, M.·Thiele, F.·Virdi, S.·Grundhoff, A.·Feschotte, C.·Roan, N. R.·Tolosa, E.·Lange, U. C.

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Abstract

People living with HIV (PLWH) on antiretroviral therapy (ART) accumulate primarily defective proviral sequences in genomes of often clonally expanded CD4+ HIV-1 target cells. The majority of viral-derived DNA is transcriptionally active and preferentially found at distinct genomic loci suggesting a selective process driven by integration site-specific crosstalk between viral and host sequences. Focusing on one of the most prominent selected integration loci, the BTB Domain and CNC Homolog 2 (BACH2) gene, we here show mechanistic insights how CD4+ T cells are functionally reprogrammed via exaptation of provirus-derived regulatory sequences during long-term ART. Using a cellular model of BACH2-integrated proviruses, we find that proviral transcription drives aberrant BACH2 protein levels that escape autoregulatory feedback and impose BACH2-dependent transcriptomic changes. By mimicking these changes in primary CD4+ T lymphocytes, we observe that BACH2 drives reprogramming of cells toward a proliferative, precursor memory-like type. These reprogrammed CD4+ T cells possess traits of immune evasion and cellular survival that are signatures of persistent HIV reservoir cells in PLWH. Inhibition of provirus transcriptional activity can mitigate exaptation, suggesting a strategy to offset HIV-driven differentiation and expansion of CD4+ T cells. Finally, our data suggest that provirus exaptation at a second prominently selected proviral integration gene, the Signal Transducer And Activator of Transcription 5B (STAT5B) gene, drives a contrary, effector-like T cell fate, suggesting a multifaceted impact of exaptation on immune homeostasis. Overall, our data suggest that transcriptionally active proviruses, even if structurally defective, modulate target cells through insertional activation of integration genes, a process which we postulate to contribute to the complex immune modulation and dysregulation experienced by ART-suppressed PLWH.

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Hamann, M. V., Brauckmann, L., Schwarz, C., Spohn, M., Stoeck, R., Leddy, S., Frouard, J., Adiba, M., Thiele, F., Virdi, S., Grundhoff, A., Feschotte, C., Roan, N. R., Tolosa, E., Lange, U. C.. 2025-09-22. Defective proviruses cause T cell reprogramming through promoter exaptation in HIV-1 infection. https://doi.org/10.1101/2025.09.22.676989

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