Hixson, Emily
(2022)
Exploration of HIV-specific Immune Responses Following Dipyridamole Treatment.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Dipyridamole is a vasodilator used to prevent heart attacks and strokes. HIV-associated reduction in extracellular adenosine levels allows for continuous immune activation in people living with HIV (PLWH). Dipyridamole inhibits the cellular uptake of adenosine via equilibrative nucleoside transporters to increase extracellular adenosine in the inflammatory milieu. We previously completed a randomized, double-blind, placebo-controlled study that showed 12 weeks of dipyridamole treatment resulted in a significant decrease in CD8+ T cell activation. Given the anti-inflammatory effects of dipyridamole, we sought to evaluate whether treatment also affected HIV-specific immune responses. We obtained cryopreserved peripheral blood mononuclear cells (PBMCs) from a subset of participants with available baseline and week 12 samples from the clinical trial. Using flow cytometry, we evaluated polyfunctional responses (defined as expression of 2 or more effector cytokines following peptide pool stimulation) to gag and env peptide pools (15mer peptides with overlapping 11 amino acids) and compared the change in response from baseline to week 12 between participants receiving dipyridamole versus placebo. We assessed whether changes in polyfunctional responses were associated with virologic, immunologic, and purinergic parameters. We evaluated virally suppressed participants with HIV (N=9 in dipyridamole arm and N=13 in placebo arm). We found a statistically significant decrease in HIV-specific CD4+ T-cell polyfunctional responses following dipyridamole treatment. Specifically, a significant decrease was observed in CD4+ T cell expression of TNFα and CD107a. Additionally, there was a trend towards decreasing polyfunctional Gag-specific CD8+ T cell responses. Furthermore, IFNγ expression was significantly decreased in HIV-specific CD4+ and CD8+ T cells. Polyfunctional responses were not associated with HIV viral persistence. However, we observed a direct correlation between T cell cycling and HIV-specific immune responses. Moreover, plasma levels of inosine inversely correlated with Gag-specific CD4+ T cell response. Although the decrease in HIV-specific immune responses was not associated with measures of HIV persistence, additional studies should focus on how modulation of the adenosine pathway can affect HIV-specific responses and the subsequent implications in HIV cure research.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
12 May 2022 |
| Date Type: |
Publication |
| Defense Date: |
22 April 2022 |
| Approval Date: |
12 May 2022 |
| Submission Date: |
28 April 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
74 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
HIV, adenosine, dipyridamole, comorbidities |
| Date Deposited: |
12 May 2022 13:13 |
| Last Modified: |
12 May 2022 13:13 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42814 |
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