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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS010687-01
Application #
2709231
Study Section
AIDS and Related Research Study Section 7 (ARRG)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1998-12-01
Project End
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
047120084
City
San Francisco
State
CA
Country
United States
Zip Code
94158