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. Interestingly, this infection was associated with a differentiation to a mature neuronal phenotype, characterized by the expression of mature neurofilaments and cell adhesion molecules, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1. Infection also induced TNF-alpha and IL-1beta mRNA expression, as well as the synthesis of inducible nitric oxide synthase by neuroblastoma cells. Exogenous addition of TNF-alpha, but not of IL-1beta or many other cytokines, including nerve growth factor, mimicked those 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 intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1. Addition of NO generators and TNF-alpha activated NF-kappaB- and intercellular cell 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-mediated mechanism.
Obregón
E
E
Division of Immunology, Hospital Universitario Gregorio Marañón, Madrid, Spain.
Punzón
C
C
Fernández-Cruz
E
E
Fresno
M
M
Muñoz-Fernández
M A
MA
D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism / Q000473:pathology*; D019898:Autocrine Communication; D002454:Cell Differentiation; D002460:Cell Line; D015497:HIV-1; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D009569:Nitric Oxide / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide