GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE304nnn/GSE304581/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304581GEOGSEfalseBACH2-integrated proviruses reprogram CD4+ T cells through LTR exaptation in HIV-1 infectionPeople 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.2026/09/28GSE304581GSM9153238GSM9153216GSM9153239GSM9153217GSM9153218GSM9153219GSM9153223GSM9153224GSM9153225GSM9153226GSM9153241GSM9153242GSM9153220GSM9153221GSM9153222GSM9153240GSM9153209GSM9153227GSM9153228GSM9153229GSM9153208GSM9153234GSM9153212GSM9153235GSM9153213GSM9153236GSM9153214GSM9153215GSM9153237GSM9153230GSM9153231GSM9153210GSM9153232GSM9153233GSM915321130173304581Homo sapiens