Work

Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses

Year: 2026

Type: article

Abstract: -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. 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 the Signal Transducer And Activator of Transcription 5B (STAT5B) selected integration gene drives a contrary, effector-like T cell fate, suggesting a multifaceted impact of exaptation on immune homeostasis. Overall, our data demonstrate that proviruses, even if structurally defective, can modulate target cells through insertional activation of integration genes, a process which we postulate to contribute to the complex immune dysregulation experienced by ART-suppressed PLWH. Significance statement: People living with HIV (PLWH) on suppressive therapy accumulate genomically integrated proviruses in HIV-1-targeted immune cells. We show that HIV proviruses can exapt viral regulatory elements to disrupt integration gene control, resulting in reprogramming of HIV-targeted CD4+ T cells toward different fates. The most prominent BACH2-integrated proviruses for example direct cells toward a proliferative, memory-like state with features of persistence and immune evasion. This mechanism demonstrates how even defective proviruses contribute to immune dysregulation in HIV-1 infection, and suggests that blocking proviral transcription may mitigate these effects in PLWH.

Source: PLoS Pathogens

DOI: 10.1371/journal.ppat.1014618