Defective HIV proviruses reprogram T cells at selected integration sites

People living with HIV on antiretroviral therapy accumulate primarily defective proviral sequences in the genomes of often clonally expanded CD4 T cells, according to a cellular and molecular study. The researchers found that a substantial share of the HIV-derived DNA is transcriptionally active and preferentially located at distinct genomic loci, supporting a selective process in which integration-site-specific interactions between viral and host sequences influence the affected cells.

The study focused on BACH2, one of the most prominent selected integration genes, and used a cellular model containing BACH2-integrated proviruses. Proviral transcription drove abnormal BACH2 protein levels that escaped the gene’s autoregulatory feedback, producing BACH2-dependent changes in the cell’s transcriptomic program. The authors describe this process as exaptation: viral sequences use regulatory features associated with a host gene to alter cellular identity and behavior.

When the investigators mimicked the relevant changes in primary CD4 T lymphocytes, BACH2 shifted the cells toward a proliferative, precursor memory-like state. The reprogrammed cells had traits associated with persistent HIV reservoir cells in people living with HIV, including immune-evasion characteristics and enhanced cellular survival. These experiments provide a mechanistic model for how transcriptionally active, defective proviruses could influence long-lived HIV target cells; they do not directly demonstrate the same causal process in people receiving antiretroviral therapy.

Inhibition of proviral transcriptional activity mitigated exaptation in the experimental system, indicating that viral transcription can be a point of intervention for reducing the modeled effects. The result does not establish a clinical strategy or show that transcriptional inhibition would reduce HIV reservoirs in people. Effects also depended on the integration site: analysis of another prominently selected gene, STAT5B, suggested that proviral exaptation there drove a contrasting, effector-like T-cell fate. The findings therefore support a locus-dependent model in which structurally defective but transcriptionally active proviruses can alter CD4 T-cell differentiation, expansion and survival through insertional effects involving host genes.

Subject of Research: Mechanisms by which defective, transcriptionally active HIV-1 proviruses alter CD4 T-cell state during antiretroviral therapy

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

Article References: Hamann, M. V., Brauckmann, L., Schwarz, C., Spohn, M., Stoeck, R., Leddy, S. M., Frouard, J., Adiba, M., Winzer, R., Hausmann, F., Virdi, S., Grundhoff, A., Feschotte, C., Sauter, D., Muecksch, F., Roan, N. R., Tolosa, E., & Lange, U. C. (2026). Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses. PLOS Pathogens, 22(10), e1014618. https://doi.org/10.1371/journal.ppat.1014618

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DOI: 10.1371/journal.ppat.1014618

Keywords: HIV-1, proviruses, CD4 T cells, antiretroviral therapy, HIV reservoir, BACH2, STAT5B, integration sites, gene regulation, immune evasion, Selective, persistence