GSBS Dissertations and Theses

ORCID ID

0000-0002-7616-7902

Publication Date

2018-07-24

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Program in Molecular Medicine

First Thesis Advisor

Jeremy Luban

Keywords

Innate immunity, dendritic cell, HIV-1, RNA export, pathogen recognition, nucleic acid detection

Abstract

Protective antiviral immune responses require priming of naïve T cells by dendritic cells (DCs) that have matured sufficiently to produce co-stimulatory cell surface molecules and cytokines. Although only low levels of productive HIV-1 infection are detected in ex vivo DCs following HIV-1 challenge, those few cells exhibit innate activation. Experimentally bypassing blocks to entry and replication leads to more efficient transduction of DCs and maturation as indicated by production of interferons and interferon stimulated genes. Furthermore, similar innate activation occurs upon transduction of macrophages or CD4+ T cells. However, the mechanism by which HIV-1 is detected to activate innate immune signaling is not clear. The purpose of this thesis is to incorporate my data and observations into the understanding of HIV-1 innate detection and attempt to resolve seemingly conflicting observations.

Reverse transcription and genomic integration are necessary for innate activation implying the need de novo transcription. Coding sequences are unnecessary save for those cis-acting sequences necessary for the HIV-1 life cycle. CRM1 dependent, HIV-1 unspliced RNA export is essential for innate activation. As intact viral sequence is unnecessary for transcription and export, defective proviruses may contribute to systemic inflammation seen in chronically infected individuals. These insights, are hoped to aid in the production of qualitatively better anti-retroviral drugs as well as in the design a protective HIV vaccine.

DOI

10.13028/75z5-2237

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

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