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ANALYSIS OF NEUROPATHOGENESIS ASSOCIATED WITH SIMIAN IMMUNODEFICIENCY VIRUS INFECTION THROUGH DIFFERENTIAL GENE EXPRESSION STUDIES

Ghosh, Mimi (2005) ANALYSIS OF NEUROPATHOGENESIS ASSOCIATED WITH SIMIAN IMMUNODEFICIENCY VIRUS INFECTION THROUGH DIFFERENTIAL GENE EXPRESSION STUDIES. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Approximately 25-30% of people infected with human immunodeficiency virus 1 (HIV-1) develop HIV-associated encephalitis and HIV-associated dementia. The underlying mechanisms leading to HIV encephalitis remain unclear. In an attempt to understand the molecular events that lead to encephalitis and subsequent dementia, I focused on identifying differentially expressed genes in the central nervous system (CNS) using SIV infected rhesus macaques as an experimental model system by using methods serial analysis of gene expression (SAGE), and microarray hybridization. I studied two different brain regions, caudate and globus pallidus, in non-infected, acutely infected, and mildly encephalitic animals. Since my analysis of macaque SAGE data utilized existing human nucleotide sequence databases, identification of the genes from which the SAGE tags were obtained proved to be challenging. I successfully identified the genes from which two of the tags were obtained. These were major histocompatibility complex class I (MHCI), differentially expressed during disease and neurogranin (Nrg), differentially expressed in caudate relative to globus pallidus. The differential expression of these two genes was confirmed by real-time RT-PCR and in situ hybridization techniques. I further characterized the localization of MHCI in the CNS tissue and found that whereas in non-infected tissues, endothelial cells were the major cell types expressing MHCI mRNA, during acute infection and mild encephalitis, when local virus replication was low or absent, all CNS cell types could express this mRNA. In addition, I observed upregulation of interferon-stimulated genes (ISGs), MxA, OAS2, and G1P3, both in the CNS and in the periphery that could be potential surrogate markers for SIV infection. Since encephalitis is observed only at end-stage disease, traditional thinking has been that the CNS remains relatively unaffected until later stages of infection. Our findings indicate that immune activation within the CNS might occur early in infection and persist in a chronic manner thereby causing continuous damage, which might affect the development of end-stage encephalitis and dementia. Therefore, early, potent, suppression of systemic viral replication could potentially inhibit the development of virus-mediated neuropathology later on. Such an approach would be of important public heath significance.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ghosh, Mimimimighosh@yahoo.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairReinhart, Toddreinhar@pitt.eduREINHAR
Committee MemberWiley, Claytonclaytonwiley@comcast.net
Committee MemberPeters, Daviddavid.peters@virgin.net
Committee MemberGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Date: 16 June 2005
Date Type: Completion
Defense Date: 18 April 2005
Approval Date: 16 June 2005
Submission Date: 22 April 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: CNS; MHCI; SAGE; SIV
Other ID: http://etd.library.pitt.edu/ETD/available/etd-04222005-145850/, etd-04222005-145850
Date Deposited: 10 Nov 2011 19:40
Last Modified: 15 Nov 2016 13:41
URI: http://d-scholarship.pitt.edu/id/eprint/7484

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