Defining Parameters for Successful Immunocytotherapy of Persistent Viral Infection

• Published in: Virology (New York, N.Y.) N.Y.), 2000-01, Vol.266 (2), p.257-263
• Main Authors: Berger, Dietmar P., Homann, Dirk, Oldstone, Michael B.A.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; AIDS/HIV; Animals; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Count; Coculture Techniques; Disease Models, Animal; g-Interferon; Humans; Immunotherapy - methods; Interferon-gamma - biosynthesis; Interleukin-2 - biosynthesis; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - therapy; Lymphocytic Choriomeningitis - virology; Lymphocytic choriomeningitis virus - immunology; Lymphocytic choriomeningitis virus - isolation & purification; Mice; Mice, Inbred C57BL; Virus Diseases - immunology; Virus Diseases - therapy; Virus Diseases - virology
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1006/viro.1999.0074

Persistent infections with viruses such as HIV, Epstein–Barr virus, cytomelagovirus, and hepatitis B and C viruses continue to be major human health problems. Immunocytotherapy for persistent viral infections has proven successful in animal models but less effective in humans. While the requirement of antigen-specific CD8+ T cells is known, the precise role of CD4+ T cells as regards specific priming, numbers needed, and interaction with CD8+ T cells is less clear. To address these issues, we used a mouse model of persistent virus infection in which adoptive transfer of T cells effectively purges virus from all tissues. We demonstrate that (1) inclusion of antigen-specific CD4+ in addition to CD8+ T cells is mandatory for efficient and long-term virus control. Neither naive nor CD4+ T cells with specificity for a different virus are sufficient. (2) The minimal numbers of virus-specific T cells required for virus clearance from sera and tissues are 350,000 virus-specific CD8+ and 7000 virus-specific CD4+ T cells or approximately 5 × 107 CD8+ and as few as 1 × 106 CD4+ T cells per square meter of body surface area, a CD8:CD4 ratio of 50:1. (3) Production of interferon-γ, obligatory for resolution of persistent infection, is dependent on the interaction of virus-specific CD4+ and CD8+ T cells. (4) Maintenance of CD8+ T cell effector functions after adoptive transfer is directly proportional to the amount of cotransferred, virus-specific CD4+ T cells.