The sanctuary for HIV-1 in the brain is formed by maintenance of virus in long-lived macrophages and microglia within the confines of the blood-brain barrier. This chronic productive infection stands in contrast to the productive form of infection in lymphocytes which is short lived and highly sensitive to antiviral intervention. The effects of antiviral therapy upon chronic infection in the brain and on the synthesis of viral and cellular neurotoxins have not been fully defined. Productive HIV of macrophage is known to activate synthesis of neurotoxin. We hypothesize that interactions of HIV-1 with macrophages which do not result in the production of infectious progeny virus, including viral replication in chronically infected cells in the presence of antiviral drugs, also induce neurotoxicity. We particularly wish to distinguish transient events driven by the interactions between viral envelope and CXCR4 or CCR5 from those arising from chronic infection in a potential viral reservoir in HIV-1 infected macrophages.
The Specific Aims are: 1. To determine the virological characteristics of the reservoir established in macrophages during chronic productive or controlled HIV-1 infection; 2. To correlate the production of neurotoxins with the expression and control of HIV-i in chronically infected macrophages. 3. To determine the ability of ligands of CCR5 or CXCR4 to activate macrophages to neurotoxin synthesis. 4. To determine the minimal interaction of HIV-1 with macrophages which activate cells to induce apoptosis in neurons. Experiments will be conducted exclusively with primary monocyte-derived macrophages. We shall monitor viral replication by PCR, Western blot, and specific immunoassays. HIV-1 infection will be arrested using viral mutants or inhibitors of reverse transcription, Tat or protease activity. Soluble neurotxins will be measured by assay of direct neuronal killing and by apoptosis in the laboratory of Dr. Gelbard and by immunoassay and Western blot. Ligation of chemokine receptors will be measured by Ca++ assays.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039191-03
Application #
6394244
Study Section
Special Emphasis Panel (ZNS1-SRB-P (01))
Program Officer
Nunn, Michael
Project Start
1999-08-01
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$278,331
Indirect Cost
Name
St. Luke's-Roosevelt Institute for Health Sciences
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10019
Saini, Manisha; Potash, Mary Jane (2014) Chronic, highly productive HIV infection in monocytes during supportive culture. Curr HIV Res 12:317-24
Li, Guanhua; Aaron, Sagiv; Kazmierczak, Katarzyna et al. (2007) Inhibition of HIV-1 or bacterial activation of macrophages by products of HIV-1-resistant human cells. Immunol Cell Biol 85:603-9
Kazmierczak, Katarzyna; Potash, Mary Jane (2007) Host and virus strain dependence in activation of human macrophages by human immunodeficiency virus type 1. J Neurovirol 13:452-61
Li, Jinliang; Bentsman, Galina; Potash, Mary Jane et al. (2007) Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection. BMC Neurosci 8:31
Saini, Manisha; Potash, Mary Jane (2006) Novel activities of cyclophilin A and cyclosporin A during HIV-1 infection of primary lymphocytes and macrophages. J Immunol 177:443-9
Sui, Ziye; Sniderhan, Lynn F; Fan, Shongshan et al. (2006) Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons. Eur J Neurosci 23:2623-34
Simm, Malgorzata; Miller, Lloyd S; Durkin, Helen G et al. (2002) Induction of secreted human immunodeficiency virus type 1 (HIV-1) resistance factors in CD4-positive T lymphocytes by attenuated HIV-1 infection. Virology 294:1-12
Chowdhury, Iqbal H; Bentsman, Galina; Choe, Wonkyu et al. (2002) The macrophage response to HIV-1: Intracellular control of X4 virus replication accompanied by activation of chemokine and cytokine synthesis. J Neurovirol 8:599-610