Heterogeneity of cytokine functions in HIV infection.

Immunological responses, especially cytokines, play important roles in determining the persistence of infectious agents in chronic diseases. Th1 responses enhance cellular immunity to control infection whereas Th2 immune responses down-regulate these effector immune responses. It has been suggested that the Th1 to Th2 switch is involved in human immunodeficiency virus (HIV) disease progression. We studied the regulatory role of interleukin-4 (IL-4; Th2 response) on interferon-gamma (IFN-gamma; Th1 response) in HIV infection and its role in the generation of HIV-specific cytotoxic T lymphocytes (CTL) in an in vitro system. Forty HIV-infected, asymptomatic individuals and 20 HIV-seronegative individuals were included in this study. Peripheral blood mononuclear cells were stimulated with phytohaemagglutinin and tetanus toxoid in the presence or absence of IL-4 to determine the effect of IL-4 on IFN-gamma production and HIV-Env-specific CTL activity. IL-4 showed a dual effect on IFN-gamma production in HIV patients. IL-4 down-regulated IFN-gamma production in HIV-seronegative individuals and in 55% of HIV patients whereas it stimulated IFN-gamma production in 45% of HIV patients. IL-4 increased HIV-Env-specific CTL activity in five of seven patients of the latter group. IL-4 has multiple biological activities, e.g. IL-4 inhibits IFN-gamma production as well as stimulates CTL generation which in turn produces IFN-gamma. Understanding the biological significance of these interactions is of importance for immunotherapeutic approaches against HIV infection.