Cellular proteomic analysis of highly exposed HIV seronegative women from the Pumwani sex worker cohort in Nairobi, Kenya
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Date
2014-09-03
Authors
Stein, Derek Riley
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Abstract
The HIV pandemic is well into its fourth decade and researchers have yet to develop a protective vaccine. The research presented in this thesis aims to identify and characterize correlates of HIV protection by studying highly exposed HIV seronegative (HESN) sex workers from Nairobi, Kenya. HESN women appear to have the natural ability to resist HIV acquisition giving the research community some hope that one-day a vaccine, microbicide or other prevention tool can be developed. Previous studies have indicated an overall immune quiescence phenotype characterized by lower immune activation in T cells and increased factors that limit HIV infection, which may play a significant role in protecting HESN women from HIV acquisition. The central hypothesis of this thesis is that quantitative shotgun proteomics of systemic and mucosal mononuclear cells from HESN women will demonstrate a proteomic profile characteristic of the immune quiescent phenotype, described by the altered expression of pathways important in immune activation, cell recruitment / migration, and proteins involved in HIV replication pathways. This hypothesis was addressed by quantifying the proteomic profile of immune cells isolated from the systemic and mucosal compartments of HESN women. In these studies HESN women were shown to have a proteomic profile representative of immune quiescence in genital tract immune cells but not systemically. Additionally, Mx2 a novel HIV restriction factor was found to be over-expressed in systemic immune cells from HESN women. These data support the role of immune quiescence in the genital tract as a potential mechanism for HIV resistance and has identified a novel HIV restriction factor that may contribute to HIV resistance in HESN women. Strategies to mimic immune quiescence at the site of HIV acquisition and regulate HIV host restriction factors such as Mx2 should be considered during future vaccine and microbicide development.
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Keywords
HIV, Proteomics