Nef and cell signaling transduction: a possible involvement in the pathogenesis of human immunodeficiency virus-associated dementia.
Although the introduction of highly active antiretroviral therapy (HAART) has resulted in a significant decrease of acquired immunodeficiency syndrome (AIDS) morbidity and mortality, the prevalence of human immunodeficiency virus (HIV)-associated dementia (HAD) has actually risen, due to the increasing life expectancy of the infected subjects. To date, several aspects of the HAD pathogenesis remain to be dissected. In particular, the viral-cellular protein interplay is still under investigation. Given their specific features, two viral proteins, Tat and Nef, have been mainly hypothesized to play a role in HIV neuropathology. Here we show that HIV-1 Nef has an effect on the transcriptional levels of a cellular protein, anaplastic lymphoma kinase (ALK), that is preferentially expressed in the central and peripheral nervous system at late embryonic stages. By its overexpression along with Nef, the authors demonstrate ALK ability to influence, at least in the U87MG astrocytic glioma cells, the mytogen-activated protein kinase (MAP-K)-dependent pathway. Moreover, although in the absence of a physical direct interaction, Nef and ALK activate matrix metalloproteinases (MMPs), which are likely to contribute to blood-brain barrier (BBB) damage in HAD. Finally, in the in vitro model of glioblastoma cells adopted, Nef and ALK show similar effects by increasing different cytochines/chemokines that may be relevant for HAD pathogenesis. If confirmed in vivo, these data may indicate that, thanks to its ability to interfere with specific cellular pathways involved in BBB damage and in central nervous system (CNS) integrity, Nef, along with specific cellular counterparts, could be one of the viral players implicated in HAD development.
Bergonzini
Valeria
V
Department of Histology, Microbiology, and Medical Biotechnologies, Division of Microbiology and Virology, University of Padova, Padova, Italy.
Calistri
Arianna
A
Salata
Cristiano
C
Del Vecchio
Claudia
C
Sartori
Elena
E
Parolin
Cristina
C
Palù
Giogio
G
D015526:AIDS Dementia Complex / Q000378:metabolism / Q000821:virology*; D000077548:Anaplastic Lymphoma Kinase; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
C515255:CXCL12 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D054311:nef Gene Products, Human Immunodeficiency Virus; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases