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Identification of Circulating Biomarkers of HIV Disease Progression

Stephenson, Katrina (2020) Identification of Circulating Biomarkers of HIV Disease Progression. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Understanding the ability of Nonprogressors (NP) to control HIV disease progression may lead to novel therapeutic strategies and vaccines, with the potential to make a significant contribution to the field of public health. A small percentage of HIV infected individuals control HIV disease progression for many years without therapeutic intervention, defined as long-term nonprogressors (NP). We have demonstrated that all professional antigen presenting cells (APC) (B cells, dendritic cells (DC) and macrophages) from NP have the unique inability to mediate HIV trans infection of autologous and heterologous CD4+T cells. We have linked this phenotype to alterations in cholesterol metabolism in APC, specifically an increased activity of the reverse cholesterol transporter ABCA-1, and to depletion of cholesterol in cell membrane lipid rafts. ABCA1 activity could be modulated by transcriptional or post transcriptional factors. Our data show that plasma from NP elicit higher cholesterol efflux from macrophages in males and females than Progressors (PR).
It was also our aim to identify soluble, circulating biomarkers that could modulate ABCA1 activity, thus being associated with control of HIV disease progression. A bioactive fatty acid screen was performed on a subset of NP and PR samples that have been well-characterized by testing for APC mediated trans infection. Analysis by liquid-chromatography-mass spectrophotometry identified metabolites present at a higher level in NP than PR, specifically 5- oxo-eicosatetranoic acid (5-Oxo-ETE). Preliminary data of 5-oxo show that treatment of APC at 5μM reduces the efficiency of HIV trans infection of CD4+T cells. A second molecule that was tested was 25-Hydroxycholesterol (25HC), which interferes with virus-cell membrane fusion and reduces inflammatory factors and cytokines. Serum from HIV infected individuals was tested for 25HC content by ELISA, and preliminary data show that 25HC levels are slightly higher in NP than PR, but more samples need to be analyzed. A trans infection assay in the presence of 25HC was also performed and it was found that treatment of B cells with 25HC in culture strongly inhibits HIV trans infection.
Genetic factors have been identified that contribute to cholesterol efflux capacity in men and women. SNPs were identified by Villard et.al. that affect the ability of macrophages to efflux cholesterol and were implicated in atherosclerotic development. These SNPs were tested in our HIV NP and PR cohorts. Two SNPs were found to be significantly associated with the male NP, contributing to differences in cholesterol metabolism and homeostasis in male and female NP and PR.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Stephenson, KatrinaKMS366@pitt.eduKMS366
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRappocciolo, Giovannagiovanna@pitt.edu
Committee MemberMartinson, Jeremyjmartins@pitt.edu
Committee MemberWendell, Stacygstacy@pitt.edu
Date: 30 July 2020
Date Type: Publication
Defense Date: 1 April 2020
Approval Date: 30 July 2020
Submission Date: 20 May 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 52
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: HIV Nonprogressors, HIV Progression, Circulating biomarkers of HIV
Date Deposited: 30 Jul 2020 20:45
Last Modified: 30 Jul 2020 20:45
URI: http://d-scholarship.pitt.edu/id/eprint/39073

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