Defining parameters for successful immunocytotherapy of persistent viral infection

Persistent infections with viruses such as HIV, Epstein-Barr virus, cytomel agovirus, and hepatitis B and C viruses continue to be major human health p roblems. Immunocytotherapy for persistent viral infections has proven succe ssful 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 c ells 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 effective ly purges virus from all tissues. We demonstrate that(1) inclusion of antig en-specific CD4(+) in addition to CD8(+) T cells is mandatory for efficient and long-term virus control. Neither naive nor CD4(+) T cells with specifi city for a different virus are sufficient. (2) The minimal numbers of virus -specific T cells required for virus clearance from sera and tissues are 35 0,000 virus-specific CD8(+) and 7000 virus-specific CD4(+) T cells or appro ximately 5 x 10(7) CD+ and as few as 1 x 10(6) CD4(+) T cells per square me ter of body surface area, a CD8:CD4 ratio of 50:1. (3) Production of interf eron-gamma, obligatory for resolution of persistent infection, is dependent on the interaction of virus-specific CD4(+) and CD8(+) T cells. (4) Mainte nance of CD8(+) T cell effector functions after adoptive transfer is direct ly proportional to the amount of cotransferred, virus-specific CD4(+) T cel ls. (C) 2000 Academic Press.