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BACH2-integrated proviruses reprogram CD4+ T cells through LTR exaptation in HIV-1 infection

ABSTRACT: People living with HIV (PLWH) on antiretroviral therapy (ART) accumulate proviral sequences in genomes of often clonally expanded CD4+ HIV-1 target cells. Viral-derived DNA is 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 evidence for exaptation of provirus-derived regulatory sequences leading to target cell reprogramming 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 HIV reservoir cells in PLWH. Finally, inhibition of LTR transcriptional activity can mitigate exaptation, suggesting a strategy to offset HIV-driven differentiation and expansion of CD4+ T cells. Overall, our data demonstrate that proviruses can modulate target cells through insertional activation of integration genes, a process which we postulate to contribute to the immune dysregulation experienced by ART-suppressed PLWH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304581 | GEO | 2026/09/28

REPOSITORIES: GEO

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