HIV-1 enters the brain early after infection and is neuropathogenic in some individuals despite generally effective antiretroviral therapy. Macrophages and microglial cells are the major target for productive infection by HIV-1 in the brain but the cellular basis for disease development is not fully defined. In the previous funding cycle of this grant, we discovered a new pattern of macrophage activation by HIV-1. We found that macrophages mount an NFkB-driven innate immune response to HIV-1 gp120 that is strain specific but not governed by coreceptor usage or virus replication The group of inflammatory genes expressed during acute responses to certain R5 and X4 HIV-1 strains is distinct from the genes expressed during the chronic response at the peak of productive infection by R5 HIV-1. In this application we propose to determine the relative contributions of the acute innate immune response and the chronic response to HIV-1 of macrophages and microglial cells to neuropathogenesis during infection in the brain. We will also investigate whether gp120 activates macrophages through interaction with a Toll-like receptor.
The Specific Aims are 1) To define distinct programs of cellular gene expression during """"""""acute"""""""" and """"""""chronic"""""""" responses of monocyte-derived macrophages to HIV-1. 2) To determine the roles of gp120 and Tat in HIV-1 induction of acute or chronic responses by MDM. 3) To determine the intermediate steps in NFkB and STAT 1 activation observed in acute or chronic responses of macrophages to HIV-1. 4) To define the predominant response of monocytes and microglial cells to HIV-1. 5) To determine whether HIV-1 infected or uninfected macrophages/microglia cells express acute or chronic response proteins in the brains of infected persons suffering had or infected persons without brain disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039191-07
Application #
6988497
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Nunn, Michael
Project Start
1999-08-01
Project End
2008-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
7
Fiscal Year
2006
Total Cost
$364,467
Indirect Cost
Name
St. Luke's-Roosevelt Institute for Health Sciences
Department
Type
DUNS #
623216371
City
New York
State
NY
Country
United States
Zip Code
10019
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