Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway.
HIV-1 enters the brain at the early stage of infection and resides primarily in a limited number of macrophages/microglia and astrocytes. Infection of these cells, however, may not explain the massive neuronal pathology which is seen in AIDS-associated dementia, suggesting a role for factors released from HIV-1 infected cells that trigger a cascade of events leading to neurodegeneration. Our results indicate that Tat, the potent regulatory protein of HIV-1 which is secreted by infected cells and can affect neighboring uninfected cells by transcellular means, can influence multiple biological events that lead to neuronal injury. These findings demonstrate that treatment of neuronal cells with Tat affects MAPK/ERK1/2 activity, the downstream central component of the nerve growth factor (NGF) signaling pathway. Furthermore, our data indicate that treatment of cells with Tat severely decreases expression of p35, a neuron-specific activator of cdk5, a cyclin dependent kinase that phosphorylates several neuronal proteins including neurofilament, and plays an important role in neuronal differentiation and survival. In parallel, Tat can bind to the cellular protein, Puralpha, which associates with cdk5. Further, results from Puralpha knockout animals revealed a decrease in p35 activity, pointing to the importance of Puralpha association with cdk5 in the activity of cdk5:p35 complex. These data demonstrate the cooperativity between HIV-1 Tat and the Puralpha in deregulation of the NGF signal transduction pathway in neuronal cells.
Peruzzi
Francesca
F
Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
Gordon
Jennifer
J
Darbinian
Nune
N
Amini
Shohreh
S
D015526:AIDS Dementia Complex / Q000473:pathology* / Q000821:virology; D002454:Cell Differentiation; D002470:Cell Survival; D015696:Gene Products, tat / Q000502:physiology*; D006801:Humans; D009414:Nerve Growth Factors / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000821:virology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D009414:Nerve Growth Factors; D054322:tat Gene Products, Human Immunodeficiency Virus