HIV: Have we solved the mystery of CD4 T-cell death?

In people living with HIV, the CD4 T lymphocyte cells (responsible for triggering the immune response), are predisposed to apoptosis, or self-destruction. But until recently, the underlying mechanism in action was poorly understood. A team from the National Institute for Scientific Research (INRS) has discovered that these cells have a higher expression of the TLR7 receptor and the IRF5 transcription factor, which constitute an “imprint” promoting cell death. In a chronic inflammatory environment, damaged tissues release molecular patterns associated with damage, such as cell components. The team observed that the TLR7 receptors detect them, then that IRF5 triggers a signal leading to cell death. Read: A health records void on gender and sexual orientation Published in JCI Insight, the study results are based on 43 adults aged 27 to 56, and may in the future be tested on infections such as COVID-19, visceral leishmaniasis, or those that can cause septic shock. Memory cells, such as CD4 T lymphocytes, allow better resistance to pathogens after a first encounter. “They are extremely important […] If you kill this memory, the person becomes more vulnerable to other infections,” saysa Simona Stäger, professor of immunology of infectious diseases at the National Institute for Scientific Research (INRS). Their death is therefore a major issue, especially for the 20% of patients for whom antiretroviral treatments do not work, and who continue to see their CD4 levels in the blood decrease. Even in people on treatment, residual inflammation persists, especially in the digestive tract. “They can cause tissue damage, and DC4 T cells are able to sense them,” says Stäger. Read: Calgary man fined $12K for selling bleach-like ‘miracle’ health product Residual inflammations can also make co-infections more risky for patients. “They have to be more careful,” says Liseth Carmona, a doctoral student at INRS. This is why "we must understand how these patients need to be treated and what is the potential target for the next remedy or the improvement of treatments", she believes. Through their research, the team demonstrated that peptides that inhibit IRF-5 are capable of blocking the transcription of this factor. "This is a sequence that can recognize the protein and prevent its activation," says Carmona. “We think peptides could be important, for example in patients with co-infections, to improve treatment outcomes.” Peptides have already been successfully tested against autoimmune diseases, such as lupus. However, the experiments of Stäger's team were carried out in the laboratory, not allowing the reactions of the human body to be observed. The peptides also blocked the entire IRF5 transcription factor in all cells. “We have to find a way to target only CD4 T cells specifically, without affecting other cells and their functions,” says Carmona. "It is too early to say how we could use it [...] Further experiments are necessary to really understand the impact it could have on other cells” notes Stäger. Finding IRF5 inhibitor peptides suitable for CD4 T cells is another challenge, according to Stäger, because this transcription factor has five different isoforms that vary depending on the genetics of the individual. The team tried different types of peptides to see which would work best. "There are always many unknown variants that we must first discover before designing a therapy," she says. The research team hopes to continue its research, in particular to investigate the possible benefits of peptides in patients for whom antiretroviral treatments remain ineffective. This article was translated from French and originally ran in our sister publication Profession Santé.

HIV: Have we solved the mystery of CD4 T-cell death?

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