2 options
CD8+ T cell effector function and transcriptional regulation during HIV pathogenesis / Demers, Korey R.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Demers, Korey R., author.
- Language:
- English
- Subjects (All):
- Immunology.
- Virology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Immunology.
- Virology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (151 pages)
- Contained In:
- Dissertation Abstracts International 78-06B(E).
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2016.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- A detailed understanding of the immune response to human immunodeficiency virus (HIV) infection is needed to inform prevention and therapeutic strategies that aim to contain the AIDS pandemic. The CD8+ Tcell response plays a critical role in controlling viral replication during HIV infection and will likely need to be a part of any vaccine approach. The qualitative feature of the CD8+ Tcell response most closely associated with immunologic control of HIV infection is its cytotoxic capacity. The pore-forming protein, perforin, is a major determinant of the cytotoxic capacity of CD8+ Tcells. In the context of chronic HIV infection, enhanced perforin expression by HIV-specific CD8+ Tcells is associated with greater control over HIV replication. However, individuals experiencing chronic progressive infection (CP) often demonstrate a diminished ability to express this important cytolytic molecule. HIV-specific CD8+ Tcells from CP also express lower levels of the T-box transcription factor T-bet, an upstream regulator of CD8+ Tcell effector differentiation and function. Whether HIV-specific CD8+ Tcells from progressors possess effector capacity during the earliest stages of infection and subsequently lose it remains unclear. The relationship between perforin, T-bet, and the closely related transcription factor eomesodermin (Eomes) also remains largely undefined in the context of acute, chronic, or controlled HIV infection. In this work, we report that CD8+ Tcell responses had high cytotoxic potential during acute HIV infection but perforin expression quickly waned with the resolution of peak viremia. Importantly, perforin was maintained in HIV-specific CD8+ Tcells with high levels of T-bet, but not necessarily in a population of T-betLo HIV-specific CD8 + T cells that expanded as infection progressed. During chronic infection there was a generalized increase in perforin expression for both total memory and HIV-specific CD8+ Tcells that was dissociated from both T-bet and Eomes. Of note, however, individuals in which perforin remained closely associated with T-bet demonstrated greater in vivo control of HIV replication. Collectively, our data imply that loss of transcriptional regulators responsible for driving strong cytotoxic responses, such as T-bet, contributes to CD8+ Tcell dysfunction during chronic progressive HIV infection.
- Notes:
- Source: Dissertation Abstracts International, Volume: 78-06(E), Section: B.
- Advisors: Michael R. Betts; Committee members: Ronald G. Collman; James A. Hoxie; James L. Riley; David B. Weiner.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2016.
- Local Notes:
- School code: 0175
- ISBN:
- 9781369510560
- Access Restriction:
- Restricted for use by site license.
The Penn Libraries is committed to describing library materials using current, accurate, and responsible language. If you discover outdated or inaccurate language, please fill out this feedback form to report it and suggest alternative language.