(Vienna, 10 June 2025) A research team led by the Medical University of Vienna has discovered a previously unknown role for the epigenetic regulator HDAC1 in chronic viral infections by using animal models. The study shows that HDAC1 specifically supports the generation of certain immune cells, which play an important role for actively fighting viruses despite chronic infection. These findings, published in the Journal of Experimental Medicine, could enable the development of new, more precise immunotherapies to combat chronic viral infections, such as HIV, hepatitis B and hepatitis C.
A long-term functional impairment of cells of the immune system, known as "T-cell exhaustion", is the focus of a lot of research into chronic viral infections, such as HIV, hepatitis B and hepatitis C. During chronic infections, CD8+ T cells, key components of the body's defence system, gradually lose their ability to fight viruses effectively. However, subgroups of these exhausted T cells are weakened to varying degrees. Remarkably, one of these groups, known as CX3CR1-positive cells, retains its immune function and is crucial for controlling the virus to some extent despite chronic infection.
The mechanism behind the emergence of these various subgroups during an infection has not yet been fully elucidated. Research teams led by Shinya Sakaguchi and Wilfried Ellmeier from the Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology at MedUni Vienna have now been able to show for the first time in an animal model that the epigenetic enzyme histone deacetylase 1 (HDAC1) is necessary to form these functionally important CX3CR1 cells. Specifically, HDAC1 influences the structure of chromatin – i.e. the degree of packaging of genetic information – in a way that enables the activation of certain genes important for the function of these CX3CR1 cells. This promotes the differentiation of exhausted T cells into the functionally important subtype. If HDAC1 is missing, chromatin structure is changed at these gene regions and these cells fail to develop. As a consequence, the amount of virus in the organism increases.
"Our findings suggest that targeted interventions in the function of HDAC1 could be used therapeutically, for example through drugs that influence its activity," says Shinya Sakaguchi, outlining a potentially new approach to the development of targeted immunotherapies. "T cell exhaustion also occurs during the immune response against cancer cells. Our results therefore also urge caution in the use of so-called pan-HDAC inhibitors, which are used in the treatment of certain types of cancer and that directly target cancer cells. These could unintentionally weaken a CD8+ T-cell subgroup that is necessary for controlling tumour growth," says Wilfried Ellmeier in anticipation of further studies that will deepen the new findings also towards human T cells and explore their full potential.
Publication: Journal of Experimental Medicine
HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection.
Ramona Rica, Monika Waldherr, Emi Miyakoda, Ana Patricia Kutschat, Marlene Schülein, Jing Zhang, Ricardo Alfredo Orbegozo-Medina, Lisa Sandner, Valentina Stolz, Darina Waltenberger, Thomas Krausgruber, Christoph Bock, Nicole Boucheron, Davide Seruggia, Wilfried Ellmeier* and Shinya Sakaguchi*.
DOI: 10.1084/jem.20240829
https://rupress.org/jem/article/222/8/e20240829/278030/HDAC1-controls-the-generation-and-maintenance-of
This research has been supported by the Austrian Science Fund (FWF).