Hidden Immune Gene Defect May Explain Kaposi Sarcoma Susceptibility

Kaposi sarcoma is a rare vascular malignancy caused by human herpesvirus 8 that typically emerges in people with compromised immunity. Yet some older, otherwise immunocompetent patients develop the disease, creating diagnostic uncertainty for clinicians. Why this subgroup is susceptible has remained unclear. Now, ne findings demonstrate a host innate immune defect that may explain vulnerability in a subset of patients.

Researchers at the Research Institute of the McGill University Health Center (Montreal, Canada) identified the first known human case of retinoic acid–inducible gene I (RIG-I) deficiency linked to Kaposi sarcoma. The defect stems from a mutation in the DDX58 gene that prevents expression of RIG-I, a key antiviral sensor. Without RIG-I, host cells fail to detect Kaposi sarcoma–associated herpesvirus (also called human herpesvirus 8), allowing infection to persist and drive oncogenic transformation.

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The investigation began with a 72-year-old, HIV-negative patient of Inuit origin who presented to McGill University Health Center with violaceous nodules of the feet and lower legs. Whole-exome sequencing pinpointed the causal DDX58 variant underlying the patient’s disease. The team then engineered experimental systems using the patient’s cells and a fluorescent Kaposi sarcoma virus to track infection in real time, demonstrating abnormal antiviral responses that permitted viral persistence and malignant reprogramming.

Mechanistic analyses indicated that the absence of functional RIG-I alters viral behavior within cells and enables survival and proliferation pathways associated with tumorigenesis. The work also expands the recognized scope of RIG-I biology: previously regarded as a detector of RNA viruses, it now emerges as critical for defense against a DNA virus, Kaposi sarcoma–associated herpesvirus. These results challenge longstanding assumptions about innate antiviral surveillance.

The authors state that the discovery may support genetic testing for patients with unexplained Kaposi sarcoma or other cancers linked to DNA viruses such as human papillomavirus (HPV), including efforts to assess how often RIG-I deficiency occurs. The findings also suggest that immunotherapies like interferon-beta—and potentially interferon-omega—could better target disease biology and be more tolerable than interferon-alpha, which is used with variable results and notable adverse effects. The study was published in the Journal of Allergy and Clinical Immunology and was conducted at the Research Institute of the McGill University Health Center.

“RIG-I was previously known for its ability to detect RNA viruses, such as those that cause influenza or COVID-19. Our work shows that it also plays a critical role in defending against Kaposi sarcoma–associated herpesvirus, which is a DNA virus. In doing so, our findings redefine its role in human antiviral immunity,” said Dr. Don Vinh, an infectious-disease specialist and microbiologist, and a scientist in the Infectious Diseases and Immunity in Global Health Program at the Research Institute of the McGill University Health Center.

"We will explore whether other components of the body's innate virus-detection mechanisms may also make some people more vulnerable to cancers caused by viruses," says Dr. Vinh. "We also hope to better understand whether genetic differences help explain why these diseases are more common in certain populations, so we can improve screening and care."

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Research Institute of the McGill University Health Center