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Elucidating T Cell Characteristics That Enable Optimal Control of HIV Replication / Yuqi Zhou.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Zhou, Yuqi, author.
- Language:
- English
- Subjects (All):
- Biology.
- Microbiology.
- Immunology.
- Virology.
- Biology--Penn dissertations.
- Penn dissertations--Biology.
- Local Subjects:
- Biology.
- Microbiology.
- Immunology.
- Virology.
- Biology--Penn dissertations.
- Penn dissertations--Biology.
- Physical Description:
- 1 online resource (115 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- HIV-infected individuals under antiretroviral therapy often have a compromised HIV-specific T cell immune response due to the lack of CD4 T cell help, viral escape, T cell exhaustion, and reduction in cell numbers due to the withdrawal of cognate antigen. A successful HIV cure strategy will involve a durable and potent force that can effectively recognize and eliminate remaining virus that may emerge from latency months, years, or perhaps decades after an individual undergoes an HIV cure regimen. T cells are ideally suited to serve in this role, but given the state of the HIV-specific T cell response, it is unclear how to best restore HIV-specific T cell activity. To compare the efficacy of TCR and CAR T cell strategies we generated engineered T cells using lentiviral vectors encoding one of three distinct HIV-specific T cell receptors (TCRs) or a previously optimized HIV-targeting chimeric antigen receptor (CAR) and compared their functional capabilities. All engineered T cells had robust, antigen-specific polyfunctional cytokine profiles when mixed with artificial antigen-presenting cells. However, only the CAR T cells could potently control HIV replication. TCR affinity enhancement did not augment HIV control but did allow TCR T cells to recognize common HIV escape variants. Interestingly, either altering Nef activity or adding additional target epitopes into the HIV genome bolstered TCR T cell anti-HIV activity, but CAR T cells remained superior in their ability to control HIV replication. To better understand why CAR T cells, control HIV replication better than TCR T cells, we performed a time course to determine when HIV-specific T cells were first able to activate Caspase 3 in HIV-infected targets. We demonstrated that CAR T cells recognized and killed HIV-infected targets more rapidly than TCR T cells, which correlates with their ability to control HIV replication. These studies suggest that the speed of target recognition and killing is a key determinant of whether engineered T cell therapies will be effective against infectious diseases.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Riley, James L.; Committee members: Guo, Wei; Lampson, Michael A.; Betts, Michael R.; Hoxie, James A.
- Department: Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381509823
- Access Restriction:
- Restricted for use by site license.
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