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Neuroprotective micrornas combat HIV-1 associated neurocognitive disorder (HAND) pathogenesis

Xiao, Renjian (2018) Neuroprotective micrornas combat HIV-1 associated neurocognitive disorder (HAND) pathogenesis. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

HIV-1 associated neurocognitive disorder (HAND) is one of the major HIV-1 co- morbidities prevalent around the world. Early during HIV-1 infection, virus crosses the blood - brain barrier (BBB) and enters central nervous system (CNS) through infiltrating infected monocytes/macrophages. These infiltrating infected monocytes/macrophages serve as the source to initiate secondary infection of resident monocytic cells and glial cells in CNS. Neurons are not directly infected by HIV-1 virus. However, pro-inflammatory cytokines and chemokines as well as viral proteins released by infected/exposed immune and glial cells are neurotoxic and contribute to the neuronal stress and apoptosis. Nearly more than half of individuals living with HIV-1 infection present with some degree of neuronal impairment. Currently, no treatment is available to prevent or treat HAND. Thus, devising a strategy to manage HAND progression and improve the quality of life in HIV-1 positive population will be highly valuable and is of great public health significance.
MicroRNAs are small non-coding RNAs which play an important role in post- transcriptional regulation. Previous studies in our laboratory have identified specific miRNAs that may have a neuro-protective role. In this study, my goal is to evaluate the role of these candidate miRNAs on inflammatory response of monocytes/macrophages and microglia during HIV-1 infection. I hypothesize that these candidate miRNAs can reduce the proinflammatory response of monocytes/macrophages and microglia, and these inhibitory effects of miRNAs are conserved during HIV-1 infection. In order to test this hypothesis, candidate miRNAs were over expressed in monocytic cell line (THP1) and microglia by using lentiviral expression vectors. Results suggest that miR-20a and miR-106b expression in monocytic cell lines inhibits TNF-α production, while miR-let-7a significantly downregulates IL-6 secretion in response to LPS either in the presence or absence of HIV-1 infection. Similarly, in microglia cells, miR-106b inhibits both IL-6 and IL-8 secretion upon LPS stimulation and miR-20a reduces IL-6 production upon TNF-α stimulation. Evaluation of these candidate miRNAs in J-Lat cells, which contain a single copy of HIV-1 latent HIV-1 virus suggest that, miR-20a, miR-106b, miR-124 and let-7a were able to reduce HIV-1 reactivation. These results indicate that neuroprotective miRNAs may have a direct role in reducing specific neuroinflammatory factor production and may also affect HIV- 1 virus production. Thus, these candidate miRNAs could have a potential therapeutic role to minimize neuroinflammatory cytokine induced neuronal dysfunction and thus aid in management of HAND.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Xiao, RenjianREX4@pitt.edurex4
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairAyyavoo, Velpandivelpandi@pitt.eduvelpandi
Committee MemberChen, Yuecheny@pitt.educheny@pitt.edu
Committee MemberJenkins, Frankfjenkins@pitt.edufjenkins
Date: 17 September 2018
Date Type: Publication
Defense Date: 24 April 2018
Approval Date: 17 September 2018
Submission Date: 5 April 2018
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 66
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: miRNA, THP1, microglia, HAND, HIV-1
Date Deposited: 17 Sep 2018 20:35
Last Modified: 17 Sep 2018 20:35
URI: http://d-scholarship.pitt.edu/id/eprint/34155

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