Primary immunodeficiency diseases (PID) are a group of more than 250 relatively rare inherited chronic disorders in which the immune system is improperly functioning, affecting one or more of its components. About one in 500 children or young adults in the United States are born with a primary immunodeficiency, mostly manifesting by recurrent viral, bacterial, fungal, or protozoal infections, severe or long lasting warts, generalized mollusca contagiosa, complications of vaccination, prolonged or recurrent diarrhoea, developmental abnormalities, autoimmunity and malignant tumors such as Kaposi's sarcoma and lymphoproliferative syndromes. A major limitation for the genetics of PID lies in the limited availability of immune cells for a molecular analysis and functional studies. We have developed protocols for the growth transformation of human T-cells in culture by a recombinant rhadinovirus based on Herpesvirus (H.) saimiri, subgroup C strain 488. This allowed for the reproducible generation of T-cell lines from more than 30 distinct clinical situations where mutations could be identified in the genes for membrane-bound ligands, cytokines and cytokine receptors, membrane-bound receptors, non-receptor protein kinases and phosphatase, adapter proteins in signaling, trafficking proteins, fusion accessory proteins, a metabolic enzyme, and transcription factors. These T-cell lines have proven useful for structural and functional analyses in diseases such as autoimmune lymphoproliferative syndrome (ALPS), Hyper-IgE-syndrome (HIES), chronic mycobacteriosis, childhood-onset Kaposi's sarcoma, epidermodysplasia verruciformis (EV), and Epstein Barr virus-associated lymphoproliferation and lymphoma.