HIV-1 infection induces differentiation of immature neural cells through autocrine tumor necrosis factor and nitric oxide production

Immature neural cell lines could be productively infected by HIV-1. Interes tingly, this infection was associated with a differentiation to a mature ne uronal phenotype, characterized by the expression of mature neurofilaments and cell adhesion molecules, intercellular cell adhesion molecule-1, and va scular cell adhesion molecule-1. Infection also induced TNF-alpha and IL-1 beta mRNA expression, as well as the synthesis of inducible nitric oxide sy nthase by neuroblastoma cells. Exogenous addition of TNF-alpha, but not of L-1 beta or many other cytokines, including nerve growth factor, mimicked t hose effects induced by infection. Moreover, blocking endogenous TNF-alpha or NO production in cultures of infected cells with a neutralizing anti-TNF -alpha antibody or inducible nitric oxide synthase inhibitors prevented the expression of the mature cell phenotype as well as expression of intercell ular cell adhesion molecule-1 and vascular cell adhesion molecule-1. Additi on of NO generators and TNF-alpha activated NF-kappa B- and intercellular c ell adhesion molecule-1-dependent promoter transcription, whereas inducible nitric oxide synthase inhibitors prevented the transcriptional activation of intercellular cell adhesion molecule-1 promoter that was induced by TNF- alpha. Those results suggest that HIV can infect immature neural cells and this infection induces their neural development via a TNF-alpha- and NO-med iated mechanism. (C) 1999 Academic Press.