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Predictive Biomarkers for the Assessment of Developing HIV-associated Neurocognitive Decline in HIV-positive Men

Joseph, Gregory (2013) Predictive Biomarkers for the Assessment of Developing HIV-associated Neurocognitive Decline in HIV-positive Men. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

The advent of Highly Active Antiretroviral Therapy (HAART) has greatly improved the control of HIV replication in infected individuals. Viral replication has become increasingly well managed and HAART has extended the time to the development of Acquired Immunodeficiency Syndrome (AIDS) for many patients. These now chronically HIV-infected individuals, while enjoying longer more healthy lives, have begun to encounter diseases that are not related to AIDS. These non-AIDS defining illnesses (NADIs) are becoming a prominent area of research and this project sought to study one such NADI, HIV-associated Neurocognitive Decline (HAND). This dementia, associated with HIV-infection, has become the focus of research seeking to understand the mechanism for the disease and also to identify risk factors for identifying patients at risk for HAND development. A pilot study was designed which sought to examine four biomarkers and assess their predictive ability for the development of HAND: single nucleotide polymorphisms (SNPs) in the RYR3 gene region and associated with Atherosclerosis, the Alzheimer’s disease risk allele APOE*4, telomere length shortening over time, and DNA methylation change were each examined in a case-control study across three sample groups: HAND+/HIV+ (cases), HAND-/HIV+ (seropositive control), HAND-/HIV- (seronegative control). The genotypes for RYR3 and APOE were assessed through Taqman and Sanger Sequencing, respectively. Absolute telomere length was assessed through quantitative PCR (qPCR) and normalized against the ribosomal single copy housekeeping gene 36B4. The methylation analysis was conducted by identifying 8 cases and matching 8 individuals to form the two control groups. Archival PBMC pellets collected at ten-year intervals were extracted from this group of 24 individuals, and their genomewide DNA methylation profile was determined via bisulfite conversion on the Methyl450 array from Illumina. It was observed that dementia status, rather than HIV serostatus, was the unifying trait that generated unexpected methylation patterns and requires further investigation. The relevance of this work in the public health field is to enable scientists to more accurately identify those at risk for developing HAND through the assessment of the four predictive biomarkers examined in this study.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Joseph, Gregorygregoryjjoseph@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMartinson, Jeremy Jjmartins@pitt.eduJMARTINS
Committee MemberFeingold, Eleanorfeingold@pitt.eduFEINGOLD
Committee MemberKingsley, Lawrence Akingsley@pitt.eduKINGSLEY
Date: 27 September 2013
Date Type: Publication
Defense Date: 8 August 2013
Approval Date: 27 September 2013
Submission Date: 23 August 2013
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 88
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: HAND, HIV, dementia, DNA methylation, HIV-associated neurocognitive decline
Date Deposited: 27 Sep 2013 16:16
Last Modified: 15 Nov 2016 14:15
URI: http://d-scholarship.pitt.edu/id/eprint/19721

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