BACH2 promotes seeding and establishment of long-lived HIV-1 reservoir in memory CD4+ T cells

  • Cell Rep Med. 2025 Aug 20:102311. doi: 10.1016/j.xcrm.2025.102311.
Hongbo Gao  1 ,  Yuhao Li  1 ,  Ritudwhaj Tiwari  1 ,  Marilia Pinzone  1 ,  Xiwen Qin  1 ,  Kolin M Clark  1 ,  Sara K Nicholson  1 ,  Tony Yao  2 ,  Kelly Rome  3 ,  Michael Scaglione  3 ,  Will Bailis  3 ,  Rachel M Presti  1 ,  Irini Sereti  4 ,  Naresha Saligrama  5 ,  Leyao Wang  6 ,  Liang Shan  7
Affiliations
  • 1. Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
  • 2. Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
  • 3. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
  • 5. Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA.
  • 6. Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA, USA.
  • 7. Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address: [email protected].
PMID: 40845840 DOI: 10.1016/j.xcrm.2025.102311
Abstract

Despite antiretroviral therapy, HIV-1 mainly persists in memory CD4+ T cells in people living with HIV-1. Most long-lived viral reservoir cells are infected by the virus near the time of therapy initiation. A better understanding of the early events in viral reservoir seeding presents opportunities for preventing latent reservoir formation. Here, we demonstrate that CD4+ T cells expressing CCR5, permissive to HIV-1 Infection, are effector or terminally differentiated cells. BTB domain and CNC homolog 2 (BACH2) is expressed by a small subset of CCR5+ cells and reverses their terminal differentiation. BACH2-mediated memory differentiation is impeded due to heightened inflammation before treatment initiation. Mice with a BACH2-knockout human immune system have a reduced frequency of HIV-1 reservoir cells and do not experience virus rebound after treatment discontinuation. Our study reveals that BACH2 is essential to the seeding and establishment of long-lived HIV-1 reservoir in memory CD4+ T cells.

Keywords
ART; BACH2; CCR5; CD4(+) T cells; HIV-1; humanized mice; memory differentiation; terminal differentiation; viral reservoirs.
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