20 September 2017
The World Health Organization estimates that chronic hepatitis B (CHB) affects around 240 million people, putting them at high risk of cirrhosis and cancer of the liver.
New treatment options for the infection may emerge from research into components of the immune system that become impaired and unable to target persistently infected cells.
Carlo Ferrari and colleagues at the University of Parma, with co-workers elsewhere in Italy, focused on the problem of specific immune system cells called CD8 T cells that become ‘exhausted’ in the chronic form of the disease. “We are looking for strategies to correct this problem,” says Ferrari. He said existing therapeutic approaches are limited and cause side-effects.
The researchers began with a widespread analysis of the activity of all the genes in virus-specific T cells isolated from patients with CHB. They looked for changes that might explain why the patients’ immunity against the virus had become impaired. This helped them identify an extensive decreased expression of genes in mitochondria—cellular organelles that supply cells with energy.
“Having identified these mitochondrial alterations, we looked for specific strategies to correct them,” says Ferrari. A promising option came in the form of antioxidant molecules that counteract ‘reactive oxygen species’, which can cause chemical damage that impairs the activity of genes and other cellular components. Treating the T cells with two promising antioxidants brought about a marked recovery in the cells’ antiviral activity. This crucial insight in studies using isolated cells leads to the hope that antioxidant therapy may prove useful as a treatment.
There are a variety of possible antioxidants to consider, focusing on those that best target mitochondria. There is also a long road of exploration and testing to travel before a possibility identified in isolated cells can lead to a safe and effective therapy in patients.
The first steps generally involve moving on to animal trials, which the researchers are considering to undertake using a virus similar to hepatitis B that infects woodchucks. These animals are not an ideal model for human hepatitis B virus, so Ferrari suggests that the team may perhaps also move directly to human trials. “This may be the most logical next step, since antioxidants targeting mitochondria have already been clinically tested in other diseases,” says Ferrari.
Fisicaro, P., Barili, V., Montanini, B., Acerbi, G., Ferracin, M. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nature Medicine 23, 327–336 (2017). | article