Project Details
Projekt
Human genetics of early onset Kaposi Sarcoma and HHV8-related neoplasia
Applicant
Dr. Philipp Peters
Subject Area
Pediatric and Adolescent Medicine
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 563845357
Kaposi's sarcoma-associated herpesvirus (KSHV) belongs to the human herpes viruses (HHV), and is also known as HHV8. It is a so-called oncovirus, for its potential to cause Kaposi’s Sarcoma (KS) and other malignancies (multicentric Castleman disease and primary effusion leukemia). KS exclusively arises in HHV8 infected individuals. KS itself is divided into different subgroups mainly based on epidemiological factors. These are classic KS (typically elderly people in the Mediterranean), endemic KS (typically children and young adults in sub-Sahara Africa), epidemic KS (seen in AIDS patients) and iatrogenic KS (seen after solid organ transplant and immunosuppression). The appearance of KS in AIDS and immunosuppression, support the hypothesis that KS arises through to insufficient immunological control of HHV8 due to a defective T cell response. On the other hand, only a small fraction of otherwise healthy individuals develops KS after infection with HHV8. This suggests, that host genetics are relevant for HHV8 control. We believe that (outside of HIV and immunosuppression) an underlying inborn error of immunity (IEI) may be the root cause of early-onset HHV8-driven malignancy. There are a handful of reports on IEI underlying KS in childhood. The group of Jean-Laurent Casanova and Vivien Béziat has recruited a large cohort of patients with classic or endemic KS, multicentric Castleman disease or primary effusion leukemia, all of them with disease onset before the age of 40 years. Via genetic sequencing this cohort will be screened for germline variants that might be causal to the observed phenotype. Already, seven candidate genes have been identified in a total of 13 patients. The candidate variants will be analyzed using computational biology and population genetics. Strong candidates will be confirmed through functional testing in-vitro using modern techniques of molecular biology and immunology. Preliminary results confirm that some of the identified variants are in fact disease causing, strongly supporting our hypothesis. Beyond identifying IEI associated with susceptibility to HHV8 and potentially discovering novel IEI, the project also aims to broaden the understanding of HHV8-driven diseases as a whole. We believe that the discovered IEI will allow us to build a framework of T cell signaling pathways crucial for HHV8 control. If we succeed, this may transform the concept of KS from a solely virus-induced malignancy to an interplay of HHV8 exposure and genetically determined susceptibility. Ultimately, this may facilitate the development of tailored therapeutic interventions.
DFG Programme
WBP Fellowship
International Connection
France
