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Dissertation
Targeting inflammation for the prevention of Human Immunodeficiency Virus (HIV) transmission and disease progression
Doctor of Philosophy (Ph.D.), Drexel University
Feb 2012
DOI:
https://doi.org/10.17918/00000727
Abstract
In HIV-1 infections, innate immune signaling results in the generation of pro-inflammatory cytokines that play an important role in determining the course of disease. However, aberrant cytokine production mediates pathological effects by increasing virus dissemination and facilitating the dysfunction/death of T lymphocytes. We have undertaken investigations to examine the effects of inhibiting immunoinflammatory signaling in the context of HIV-1 transmission and chronic disease. Initially, we determined whether suppressing inflammation and simultaneously inhibiting viral infectivity would mediate protection against HIV-1 infection. This led to the development of PDB oligomers as dual-acting microbicides that inhibit HIV-1 infection and also dampen inflammation. PDB compounds were potent anti-inflammatory agents through their TLR7/9-specific antagonistic properties. In addition, as anti-HIV inhibitors, PDBs prevented reverse transcription. Importantly, intravaginal application of PDB delayed mucosal acquisition of SHIV in rhesus macaques. These data suggest that PDB-based compounds may be promising microbicide candidates for clinical development. A pro-inflammatory cytokine environment during chronic HIV-1 infection favors a hyperimmune activation state that leads to T cell exhaustion and depletion. Because type I IFN production distinguishes pathogenic and non-pathogenic AIDS virus infections, we examined how IFN[alpha]/[beta] can prime T cells in HIV-1 infection to undergo apoptosis. The mitochondrial death mediator Bak was increased in patients and correlated positively with sensitivity to CD95/Fas-mediated T cell apoptosis and negatively with CD4+ T cell counts. Importantly, IFN[alpha]/[beta] increased Bak expression and CD95/Fas-induced apoptosis in T cells from healthy donors. IFN[alpha]/[beta] further primed T cells, including HIV-specific CD8+ T cells from patients to CD95/Fas-mediated death. HIV-1 exposure sensitized T cells to CD95/Fas-induced apoptosis, which was IFN[alpha]/[beta]-dependent. In HIV-1-infected patients, an IFN[alpha]-stimulated gene signature correlated positively with ex vivo Bak levels and CD95/Fas-mediated apoptosis, but negatively with CD4+ T cell counts. Plasma IFN[alpha] was also inversely correlated with CD4+ T cell counts in chronic SIV infection. Finally, in SIV-infected rhesus macaques, plasma IFN[alpha] and viral loads correlated negatively during acute infection suggesting an antiviral effect, but positively during chronic infection indicating that virus may drive type I IFN. Therefore, type I IFN generated during chronic HIV-1 infection may contribute to the loss of T cells and disease progression.
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Details
- Title
- Targeting inflammation for the prevention of Human Immunodeficiency Virus (HIV) transmission and disease progression
- Creators
- Joseph A. Fraietta
- Contributors
- Peter D. Katsikis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xviii, 151 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014970204104721