This study is conducted in collaboration with Dr. Olimpia, Meucci, which is the project leader. Dr. Meucci is supported by the grants R01-DA15014-06 and R01-DA19808 from the National Institutes of Health (NIDA).
HIV infection is associated to dementia in approximately 20% of individuals. As no convincing evidence exists that neurons are infected by the HIV, neuronal death seems likely induced through receptor-mediated mechanisms.
CXCR4 and CCR5 chemokine receptors bind gp120 envelope protein and function as co-receptors for the HIV infection of immune cells. Dr. Olimpia Meucci has recently demonstrated that rat hyppocampal neurons express several chemokine receptors and recombinant gp120 can induce neuronal death while chemokines protect from gp120-induced neurotoxicity in vitro.
In collaboration with Meucci’ group, we are currently attempting to characterize chemokine receptor functioning, including dimerization, internalization, changes in conformation and activation of downstream substrates in rat and human neurons in culture. Chemokine receptors dimerize upon binding with their agonist and this process is crucial for signaling. Crosslinking studies are performed in order to detect possible differences in receptor dimerization in response to chemokines and gp120. Co-immunoprecipitation is used to ask whether chemokine receptors interact with different sets of downstream substrates, such as GTP-binding proteins, following binding to chemokines and gp120.
We also aim to determine whether gp120 neurotoxicity is associated with perturbation of the cell cycle. Thus, we are investigating whether gp120 binding to chemokine receptors triggers the activation of proliferative pathways in terminally differentiated neuronal cells. For the same reason, we are exploring potential effects of gp120 on the expression of cyclin D1 and other oncogenes involved in G1 cell cycle progression.