HIV-1 -induced neurological dysfunctions represent a complex series of events which result fiom direct and indirect communication between virus and host cells in the brain. The direct mechanism includes replication of HIV-1 in microglia, and to a lesser degree in astrocytes, whereas the indirect pathway involves viral and cellular secretory factors that impact upon neurons and other brain cells. In both events, a cascade of regulatory reactions including signal transduction plays a pivotal role in derailing cell functions that are manifested by pathological features such as apoptosis of neuronal and astrocytic cells; demyelination; and abnormal morphological appearance of various cells within the Central Nervous System (CNS). In this program project, we focus our attention on signal transduction pathways that have a potential in modulating direct and indirect pathways involved in the genesis of neuropathology in AIDS brain. In project 1 (Drs. Amini, Peruzzi), experiments are proposed to investigate the effect of viral regulatory protein, Tat and cellular modulators secreted by the infected cells upon NGF and its downstream effectors in neuronal cells. More specifically, experiments are proposed to investigate functional and physical interactions of factors within MAP kinase pathway with cdKYp35, the important regulator of neuronal cell differentiation and survival. In project 2 (Drs. Reiss, Rappaport), studies will be carried out to assess reciprocal talk between Tumor Necrosis Factor-alpha (TNF-alpha), and Insulin Growth Factor (IGF) pathways during neuronal cell differentiation. More specifically, we will investigate the mechanism whereby TNF- alpha via activation of Caspase 8 counteracts anti-apoptotic activity of IGF-mediated signaling in CNS cells. In project 3 (Drs. Sawaya, Khalili), the emphasis will be on the role of Wnt and TGF-beta signal transduction pathways in control of HIV-1 gene expression and replication in microglia and astrocytes. More specifically, the cooperative interaction of Tat with the key components of Wnt pathway, which includes TCF-4 and beta-Catenin, and the functional interaction of Smads, the critical downstream regulators of TGF-beta, and C/EBP, a transcription factor that bridges both Wnt and TGF-beta regulatory function, will be explored. The Neuropathology and Tissue Culture Core (Drs. Del Valle, Gordon), will provide a unique infrastructure to study clinical samples for the various components of the signal transduction pathways which are subject for deregulation by HIV-1 in brain, and determine the biological relevance of the results from the three projects with the pathological reality. Further, this core will be a reliable source for preparation and distribution of various neural cells. The participants of this program project who have worked synergistically to study HIV-1-CNS interactions during the last five years, will be able to convert the information fiom these molecular studies to understand the basic mechanisms that dictate neuronal cell differentiation and death, and utilize the outcome of this for devising molecular therapeutic strategies to block viral replication, and improve neuronal vitality during the course of the disease.
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