Defining parameters for successful immunocytotherapy of persistent viral infection.
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 x 10(7) CD8(+) and as few as 1 x 10(6) CD4(+) T cells per square meter of body surface area, a CD8:CD4 ratio of 50:1. (3) Production of interferon-gamma, 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.
Berger
D P
DP
Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California, 92037, USA.
Homann
D
D
Oldstone
M B
MB
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002452:Cell Count; D018920:Coculture Techniques; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000628:therapy / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000302:isolation & purification; D051379:Mice; D008810:Mice, Inbred C57BL; D014777:Virus Diseases / Q000276:immunology / Q000628:therapy* / Q000821:virology
D007376:Interleukin-2; D007371:Interferon-gamma