Abstract

Microglia are main targets of HIV-1 in the CNS, and neurological disease (HAD/HIVE) occurs as a result of interaction between HIV-1 and glial cells leading to neuronal apoptosis. Studies from the previous funding period have demonstrated that in the CNS of HIVE and in primary cultures of human glia, activated microglia express IL-1 which induces astrocyte TNFalpha and INOS, resulting in neuronal apoptosis. IFNbeta downregulates inflammatory activation of glial cells and induces anti-HIV-1 beta-chemokines (RANTES, MIP-1beta and MIP-1alpha), suggesting a role for IFNbeta as a therapy for HIVE. In addition to IFNbeta, a number of macrophage to the inhibitory effect of exogenous beta-chemokines diminishes under these conditions. Furthermore, beta-chemokines are induces in HIV-1 infected microglia by mechanisms linked to viral replication and MAP kinases play differential roles in IFNbeta- and HIV-induced beta-chemokine expression. Cytokine-induces apoptosis of primary human neurons occurs via caspases-dependent mechanisms and IFNbeta exhibits an anti-apoptotic property in this system. Based on these findings, we propose the following specific aims.
Specific Aim 1 : To determine the role of macrophage activators in HIV-1 infection of microglia.
Specific Aim 2 : To determine the mechanism of RANTES induction in human glia.
Specific Aim 3 : To determine the role of IFNbeta/chemokines in cytokine- or HIV-mediated neurotoxicity and to examine the role of caspases in these processes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH055477-06A2
Application #
6409062
Study Section
Special Emphasis Panel (ZRG1-AARR-6 (01))
Program Officer
Joseph, Jeymohan
Project Start
1995-09-30
Project End
2006-05-31
Budget Start
2001-07-19
Budget End
2002-05-31
Support Year
6
Fiscal Year
2001
Total Cost
$360,800
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Suh, Hyeon-Sook; Lo, Yungtai; Choi, Namjong et al. (2015) Insulin-like growth factors and related proteins in plasma and cerebrospinal fluids of HIV-positive individuals. J Neuroinflammation 12:72
Tarassishin, Leonid; Suh, Hyeon-Sook; Lee, Sunhee C (2014) LPS and IL-1 differentially activate mouse and human astrocytes: role of CD14. Glia 62:999-1013
Tarassishin, Leonid; Casper, Diana; Lee, Sunhee C (2014) Aberrant expression of interleukin-1? and inflammasome activation in human malignant gliomas. PLoS One 9:e103432
Suh, Hyeon-Sook; Lo, Yungtai; Choi, Namjong et al. (2014) Evidence of the innate antiviral and neuroprotective properties of progranulin. PLoS One 9:e98184
Suh, Hyeon-Sook; Gelman, Benjamin B; Lee, Sunhee C (2014) Potential roles of microglial cell progranulin in HIV-associated CNS pathologies and neurocognitive impairment. J Neuroimmune Pharmacol 9:117-32
Tarassishin, Leonid; Lim, Jihyeon; Weatherly, D Brent et al. (2014) Interleukin-1-induced changes in the glioblastoma secretome suggest its role in tumor progression. J Proteomics 99:152-168
Lutz, Sarah E; González-Fernández, Estibaliz; Ventura, Juan Carlos Chara et al. (2013) Contribution of pannexin1 to experimental autoimmune encephalomyelitis. PLoS One 8:e66657
Tarassishin, Leonid; Lee, Sunhee C (2013) Interferon regulatory factor 3 alters glioma inflammatory and invasive properties. J Neurooncol 113:185-94
Suh, Hyeon-Sook; Zhao, Meng-Liang; Derico, Leandra et al. (2013) Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators. J Neuroinflammation 10:37
Tarassishin, Leonid; Bauman, Avital; Suh, Hyeon-Sook et al. (2013) Anti-viral and anti-inflammatory mechanisms of the innate immune transcription factor interferon regulatory factor 3: relevance to human CNS diseases. J Neuroimmune Pharmacol 8:132-44

Showing the most recent 10 out of 65 publications