HIV-associated CNS disease is thought to result indirectly from a toxic mediator produced by HIV-infected macrophages in the CNS. The exact nature of this putative indirect action remains poorly characterized, as does the basic understanding of CNS macrophage development and function in non- infected brains. The overall hypothesis of this proposal is that HIV infection of CNS macrophages (microglia) or their precursors leads to neuronal cell death. Assuming that HIV-infected microglia influence neuronal cell death, we plan to systematically elucidate the mechanism of this effect. Potential mechanisms we will investigate include: a) interaction of HIV envelope glycoproteins (gp120 and gp41) with chemokine receptors on neurons; b) up-regulation via an HIV-encoded regulatory protein (tat) of soluble mediators (interleukins IL-1, IL-6, tumor necrosis factor (TNFalpha), interferon (IFNgamma), excitatory amino acids and nitric oxide (NO)) in microglia which may result in neuronal death; and 3) up-regulation of microglial surface proteins (Fas, ICAM-1) that may mediate neuronal apoptosis (programmed cell death).
The specific aims are: 1) to establish a model human CNS system in which the microglial population can be accurately assessed; 2) to evaluate whether reconstitution of human fetal CNS tissue with HIV-infected human microglia results in neuronal death; 3) to evaluate the mechanism(s) by which the HIV-infected human microglia cause neuronal cell death in vitro; and 4) to demonstrate whether putative microglial mediators of HIV-associated neuronal death can be inhibited in vivo. Ultimately our goal is to develop in vitro and in vivo model systems for HIV-associated CNS disease to conduct better inquiries into the pathophysiology and therapeutics of disease.
