Lipopolysaccharide-induced HIV-1 expression in transgenic mice is mediatedby tumor necrosis factor-alpha and interleukin-1, but not by interferon-gamma nor interleukin-6

Background: As serum HIV-1 load correlates well with the prognosis of the d isease, it is suggested that the viral load is one of the major determinant s of the disease progression of AIDS. Accordingly, HIV-1 activation mechani sms were extensively studied in vitro, and involvement of cytokines includi ng tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6 and interfer on (IFN)-gamma has been suggested in this process. However, so far the role s of these cytokines in the HIV-1 expression in vivo have not been well elu cidated because of the lack of appropriate animal disease models. Objective: To elucidate the roles of cytokines in HIV-1 activation in vivo. Design and methods: Transgenic mice carrying a defective HIV-1 genome were used as a model for HIV-1 carriers. In order to examine the possible involv ement of cytokines in HIV-1 expression, TNF-alpha-, IL-1- IL-6- and IFN-gam ma-deficient HIV-1 transgenic mice, were produced and HIV-1 expression was analyzed after activation with bacterial lipopolysaccharides(LPS). Results: HIV-1 expression in the transgenic mouse spleen was activated 10- to 20-fold by LPS, and the serum p24 Gag protein levels reached 400 pg/ml, which is nearly equal to the levels that occur in AIDS patients. However, t his augmentation was suppressed by 60% in TNF-alpha-deficient mice and by 4 0% in IL-1 alpha/beta-deficient mice. In contrast, no suppression was obser ved in either IL-6-, IFN-gamma-, IL-1 alpha, or IL-1 beta-deficient mice. Conclusions: Results suggest that TNF-alpha and IL-1 play important roles i n HIV-1 gene activation and selective suppression of these cytokines could improve clinical prognosis and potentially slow progression of the disease. (C) 2000 Lippincott Williams & Wilkins.