Kristoff, Jan
(2019)
Programming dendritic cells for the 'kick and kill' of latent HIV-1.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Finding a nontoxic, effective means to purge the latent HIV-1 reservoir in virally suppressed individuals undergoing antiretroviral therapy (ART) remains a major obstacle to a functional cure. The ‘kick and kill’ approach to controlling HIV-1 involves induction of HIV-1 latency reversal (LR) during ART to expose infected cells, while creating an arsenal of immune effector cells, such as cytotoxic T lymphocytes (CTL), capable of eliminating these targets. While pharmacological latency reversal agents (LRAs) have achieved limited success in ex vivo studies, none have been shown to reduce the latent reservoir in HIV-1-infected individuals. In addition, some LRAs have been shown to negatively impact antigen-specific CD8+ T cell effector responses in vitro. An optimal cure strategy must address not only induction of proviral gene expression but also clearance of reactivated cells presenting HIV-1-associated peptide epitopes by either highly functional CTL, or through incorporation of other immune-based strategies, including broadly neutralizing antibodies, T cell vaccines, or compounds modulating pro-apoptotic pathways. Conventional dendritic cells (DC) have been safely and widely used in HIV-1 clinical trials for their capacity to induce antigen-specific T cell responses, but their HIV-1 LRA potential has been underexplored. In this dissertation, I show that antigen-presenting monocyte-derived DC generated from chronic HIV-1-infected individuals on ART were shown to induce HIV-1 LR in autologous CD4+ T cells in an antigen-dependent manner. The LRA activity of DC does not appear to be a function of unidirectional communication from DC to CD4+ T cells, as DC-mediated LR was enhanced by bidirectional signaling events resulting from DC:CD4+ T cell cross-talk and sharply diminished by blockade of the CD40L/CD40 helper signaling pathway. Importantly, these data demonstrate the potential of this DC-based therapeutic to promote both the antigen-specific exposure and CTL killing of exposed CD4+ T cells harboring replication-competent provirus. Of public health significance, strategic inclusion of virus-associated MHC class II helper antigens in DC-based HIV-1 immunotherapies could serve both as a targeted means to safely unmask virus antigen-specific CD4+ T cells harboring HIV-1, and to support CTL responses that effectively target the DC-exposed latent reservoir as a functional cure strategy.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 June 2019 |
| Date Type: |
Publication |
| Defense Date: |
24 April 2019 |
| Approval Date: |
26 June 2019 |
| Submission Date: |
4 April 2019 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
177 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
HIV-1 latency reversal, dendritic cells, cytomegalovirus, T cells, CD40 ligand, immunotherapy |
| Date Deposited: |
26 Jun 2019 18:41 |
| Last Modified: |
01 May 2021 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/36286 |
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