Papillomavirus. © Inserm/U190

Most of us carry human papillomaviruses (HPVs) – particularly skin papillomaviruses that generally cause warts or benign local lesions. However, on very rare occasions worldwide patients develop severe forms of these viral diseases, including “tree man” syndrome. This highly debilitating disease manifests as the uncontrolled growth of horn-like skin lesions for which surgery is ineffective. As part of an international collaboration, researchers from Inserm, teacher-researchers from Université de Paris, and doctors from AP-HP, all grouped at the Imagine Institute (Inserm/Université de Paris, Paris hospitals group AP-HP) located at Necker Hospital for Sick Children AP-HP, have been the first to reveal a genetic cause of tree man syndrome. This research was conducted by Vivien Béziat, under the supervision of Profs. Jean-Laurent Casanova and Laurent Abel, who run a laboratory with branches in Paris and New York’s Rockefeller University1. It was published on July 1, 2021, in the journal Cell.

There are over 200 human papillomaviruses (HPVs), with some causing benign skin lesions such as common or plantar warts, and others with the potential to cause cervical cancer. The Human Genetics of Infectious Diseases laboratory has focused on skin HPVs, working for several years to understand why these usually harmless infections take a severe turn in a few very rare cases.

A genetic mutation increases susceptibility to skin papillomaviruses

In a publication in the journal Cell, the team of Vivien Béziat, Inserm researcher in the Human Genetics of Infectious Diseases laboratory and first author of the publication, studied the genetic characteristics of an Iranian patient with tree man syndrome, and two members of his family presenting with a severe skin HPV infection involving large numbers of warts on their hands and feet, but who had not developed the syndrome. What the three patients were found to have in common was a mutation of the CD28 gene, which usually plays a major role in activating T cells – the immune cells that destroy the cells infected by a virus.

In these patients, the CD28 gene mutation prevents the immune system from recognizing the virus and from mounting an appropriate response. The virus then proliferates in the keratinocytes, the cells that make up the skin’s epidermis, causing the uncontrolled multiplication of skin warts and/or horn-like lesions. This is the first time that a genetic cause of tree man syndrome has been identified.

The CD28 gene, central for resisting certain skin papillomaviruses, but not for the immune system

However, it was when analyzing the CD28 mutation that the researchers made a different discovery. The CD28 gene, until now considered a mainstay in immune system function and T cell response, does not appear to play such a major role. The medical histories of the three patients showed exposure to several HPV types and to a very large number of other pathogens. Yet only the patient with tree man syndrome developed a severe reaction to HPV2, and only the two members of his family did so to HPV4.

“These patients only showed abnormally high susceptibility to certain papillomaviruses of the gamma-HPV and alpha-HPV genus. Based on the work done over the past 30 years, we thought that a CD28 gene dysfunction would actually make patients susceptible to many infectious agents. But even if their immune response is weakened, the patients defend themselves well against other pathogens,” explains Béziat.

A discovery which therefore provides new insights into genetic susceptibility to HPVs and challenges the dogmas of T cell-mediated immune response.

“No treatment has so far been shown to be effective against tree man syndrome”. A hematopoietic stem cell transplant to replace the patient’s immune system is being considered. However, this major, costly treatment is not easily accessible to populations living in less developed countries, who will progress towards very severe forms of the disease, notably due to lack of access to care. By advancing research, the team hopes to accelerate access to treatment for these patients.

1 The Human Genetics of Infectious Diseases laboratory is directed by Jean-Laurent Casanova and Laurent Abel and is located at the Imagine Institute in Paris and Rockefeller University in New York. At both branches, Casanova heads up genetics and experimental immunology, whereas Abel heads up genetics and mathematical epidemiology.

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