Date of Award

12-1-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Graduate School of Biomedical Sciences

First Advisor

Anuja Ghorpade

Abstract

This dissertation explores the role of chemokine CXCL8 during human immune deficiency virus (HIV)-1 infection in the brain. Chemokine CXCL8 is an important neutrophil chemoattractant implicated in various neurodegenerative disorders. It is upregulated in the brains and cerebrospinal fluid of HIV-1 infected individuals suggesting its potential role in HIV-1 associated neuroinflammation. Astrocytes are known to be the major contributors to the CXCL8 pool. Interleukin (IL)-1β activated astrocytes exhibit significant upregulation of CXCL8.

In order to determine the signaling pathways involved in CXCL8 regulation in astrocytes, we employed pharmacological inhibitors for non-receptor Src homology-2 domain-containing protein tyrosine phosphatase (SHP) 2 and mitogen-activated protein kinases (MAPK) pathway and observed reduced expression of CXCL8 following IL-1β stimulation. Thus, our findings suggest an important role for SHP2 in CXCL8 expression in astrocytes during inflammation, as SHP2, directly or indirectly, modulates p38 and extracellular signal regulated kinase (ERK) MAPK in the signaling cascade leading to CXCL8 production.

In the post-antiretroviral therapy (ART) era, low level of productive replication of HIV-1 in brain is a critical component of neuropathogenesis regulation. HIV-1 replication is a complex mechanism involving both host and viral factors. The majority of viral replication in brain occurs in perivascular macrophages and/or 2 microglia. In this study, we investigated the effect of CXCL8 on productive infection of HIV-1 in human monocytes-derived macrophages (MDM) and primary human microglia. The results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2 and induces HIV-1 long terminal repeat (LTR) promoter activity.

Detailed understanding of astrocyte signaling and HIV-1 replication, as presented in the thesis, will be relevant to glial-neuronal interactions, which are central to neuroinflammation in HIV-1 and many other neurodegenerative conditions. Also, modulation of levels of CXCL8 can be a therapeutic strategy for control of productive HIV-1 replication in the brain

Comments

Mamik, Manmeet K., Chemokine CXCL8 mediated intercellular interactions in HIV-1 associated dementia. Doctor of Philosophy (Biomedical Sciences), Nov 2013, 135 pp., 233 bibliographies Available online December 2014

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