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Role of HIV-1 Vpr on Host-Cellular Functions: Cell-Specific Analysis in Productively-Infected Macrophages

Sparks, Jessica (2013) Role of HIV-1 Vpr on Host-Cellular Functions: Cell-Specific Analysis in Productively-Infected Macrophages. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Progression of human immunodeficiency virus type 1 (HIV-1) pathogenesis impedes on the patient’s ability to combat foreign pathogens by infecting immune cells, a disease commonly referred to as acquired immunodeficiency syndrome (AIDS). In addition to the onset of AIDS, HIV-1 is known to cause other health issues over time, including cardiovascular disease, premature aging, neurocognitive impairment, and dementia. The quality of life for HIV-1-positive patients has drastically increased with the introduction of highly active anti-retroviral therapies (HAART). Though the use of HAART treatments lower the incidence of HIV-1-associated comorbidities, including dementia, more understanding on HIV-1-associated comorbidities is necessary to help further improve the quality of life for HIV-1-positive patients, which is of considerable public health significance.
This study focuses on the role of the HIV-1 accessory protein viral protein R (Vpr) in HIV-1 pathogenesis. Previous studies in our laboratory have established a role for Vpr in HIV-1 immunopathogenesis and neuropathogenesis, particularly in the modulation of cytokines and chemokines, including IL-8 and IL-1β, in monocyte-derived macrophages and dendritic cells. These proinflammatory cytokines were additionally found to cause immune dysregulation and neuronal injury. As a result, this study focuses on understanding the origin of these cytokines within subpopulations of monocyte-derived macrophages: productively-infected macrophages that are actively producing virions and non-productively-infected macrophages, which include latently-infected macrophages, uninfected macrophages, and macrophages exposed to virus particles and viral proteins. In order to distinguish between the two groups, reporter viruses were created that are capable of infecting macrophages and expressing the enhanced green fluorescence protein (EGFP) upon replication. Productively-infected macrophages were successfully identified from non-productively-infected macrophages by utilizing EGFP expression, which allowed for cell-specific analysis of cytokine expression within the macrophage subpopulations. Productively-infected macrophages yielded a decrease in IL-8 and IL-1β when infected with Vpr-deficient (∆Vpr) reporter viruses, while non-productively-infected and exposed macrophages showed no noticeable difference. Similarly, a virion association defective mutant of Vpr (Vpr-A30L) resulted in lower amounts of IL-8 expression. These results elucidate the distinct role of Vpr in IL-1β and IL-8 expression in the virion-associated forms and during de novo synthesis in productively-infected macrophages.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sparks, Jessicajks44@pitt.eduJKS44
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairAyyavoo, Velpandivelpandi@pitt.eduVELPANDI
Committee MemberMartinson, Jeremyjmartins@pitt.eduJMARTINS
Committee MemberDi, Peterpeterdi@pitt.eduPETERDI
Date: 27 September 2013
Date Type: Publication
Defense Date: 24 July 2013
Approval Date: 27 September 2013
Submission Date: 22 July 2013
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 108
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-1 Vpr Macrophage Pathogenesis Cytokine Chemokine Productive Infection
Date Deposited: 27 Sep 2013 14:49
Last Modified: 01 Sep 2018 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/19575

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