Background:  HIV-associated dementia (HAD) is the most common cause of dementia in AIDS patients worldwide and is considered one of the independent risk factors for death due to AIDS. During early infection, HIV-1 enters the Central Nervous System (CNS) and resides in macrophages/microglia. Although HIV replicates in these cells, macrophages/microglia do not support a high level of virus replication, suggesting that virus replication is not the only cause of neurodegeneration and HAD. These observations suggest that viral and cellular factors associated with HIV-1 infection could be the leading cause of neuronal degeneration and pathogenesis. Furthermore, recent studies indicate that cellular proteins such as chemokines/cytokines, neurotoxins, and HIV-1 viral proteins gp120, Tat, Nef, and Vpr are the causative agents of HAD. However, the mechanisms involved in induction of HAD by cellular or viral factors are unknown. Here we have evaluated HIV-1 Vpr mediated apoptosis and neurodegeneration and the role Vpr interacting host cellular proteins may play in HAD. 

Methods:  In a yeast-2 hybrid system, using Vpr as bait and a cDNA library derived from brain tissue as prey, we have identified a novel gene product, Vpr-binding Brain Protein (VBP), as a Vpr-interacting protein. To understand the interaction between these two proteins and their downstream effects on host cellular pathology, we have performed protein-protein interaction studies and functional assays utilizing siRNA to identify the role of VBP in neurons.

Results: Results from GST pull-down and co-immunoprecipitation assays indicated that Vpr and VBP exhibit a physical interaction.  Structural analysis has revealed that VBP has numerous protein interaction domains and is present in several isoforms. In the presence of Vpr, VBP displayed a differential sub-cellular distribution pattern during localization studies. Gene silencing analysis revealed that VBP is essential for neuronal cell survival, because blocking the production of this gene product in neuronal cells triggered apoptosis.

Conclusions:  These results indicate that the interaction between Vpr and VBP might play an important role in neuronal pathogenesis. Further mapping and functional studies may reveal the mechanisms involved and lead to the development of therapeutics effective in the prevention and treatment of HAD.

Keywords: HIV-1 Vpr; HAD; protein interaction