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Mucosal and Systemic Immune Phenotype Is Altered

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Mucosal and Systemic Immune Phenotype Is Altered MUCOSAL AND SYSTEMIC IMMUNE PHENOTYPE IS ALTERED DURING HIV-1 INFECTION AND IS PARTIALLY RESTORED AND FURTHER DISRUPTED IN THE ABSENCE OF DETECTABLE VIRAL REPLICATION by MARIE ROSE MCCAUSLAND Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Molecular Biology and Microbiology CASE WESTERN RESERVE UNIVERSITY January, 2017 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Marie Rose McCausland candidate for the Doctor of Philosophy* Committee Chair John Tilton Committee Member David McDonald Committee Member Calvin Cotton Committee Member Alan Levine Date of Defense July 25, 2016 *We also certify that written approval has been obtained for any proprietary material contained therein ii This dissertation is dedicated to my loving and amazing husband Jeffrey Alexander McCausland. iii Table of Contents List of Tables ........................................................................................................................ ix List of Figures ....................................................................................................................... x Acknowledgements ............................................................................................................... 1 Abbreviations ........................................................................................................................ 3 Abstract ................................................................................................................................. 5 Chapter 1: Introduction ............................................................................................................. 7 HIV ........................................................................................................................................ 8 The Epidemic .................................................................................................................... 8 The Virus and Viral Life Cycle ......................................................................................... 9 The Advent of Combination Antiretroviral Therapy ....................................................... 13 Living with HIV in the Treatment Era- Immune successes and Immune failures .......... 17 Increased plasma indices of inflammation and correlation to increased morbidity and mortality ..................................................................................................................................... 18 Monocytes in Disease .......................................................................................................... 18 Intestinal Barrier Function and Intestinal Epithelial Cell Polarity ...................................... 20 Intestinal Barrier function is decreased in HIV disease ...................................................... 23 Toll-Like Receptors ............................................................................................................. 25 The Microbiome .................................................................................................................. 28 Mucosal Immune cells depleted in HIV disease and our resulting model of systemic inflammation .............................................................................................................................. 29 v Chapter 2: Altered Monocyte Phenotype in HIV-1 Infection Tends to Normalize with Integrase-Inhibitor-Based Antiretroviral Therapy ......................................................................... 32 Summary ............................................................................................................................. 33 Background .................................................................................................................... 33 Methods .......................................................................................................................... 33 Results............................................................................................................................. 33 Conclusions .................................................................................................................... 34 Introduction ......................................................................................................................... 34 Results ................................................................................................................................. 35 Patient and Control Samples ........................................................................................... 35 Monocyte Phenotypes in Fresh and Cryopreserved PBMCS .......................................... 36 Altered Proportions of Monocyte Subsets in Untreated HIV-1 Infection ....................... 37 Monocyte Phenotypes are Altered in Untreated HIV-1 Infection and Change with ART ............................................................................................................................................... 38 Greater HLA-DR Expression and Density in Untreated HIV-1 Infection, Tend to Decrease with ART ................................................................................................................ 38 Greater CD86 Expression and Density on Monocytes in Untreated HIV-1 Infection decrease with ART ................................................................................................................. 39 Lower CD40 Density on Traditional Monocytes in Untreated HIV-1 Infection ............. 40 Chemokine Receptor (CCR2 and CX3CR1) Expression on Inflammatory and Patrolling Monocyte Subsets is Lower in Untreated HIV-1 Infection and Normalizes with ART ........ 41 Discussion ........................................................................................................................... 43 vi Methods ............................................................................................................................... 46 Ethics Statement .............................................................................................................. 46 Study Design ................................................................................................................... 47 Sample Collection ........................................................................................................... 47 Flow Cytometry ............................................................................................................... 48 Statistics........................................................................................................................... 49 Chapter 3- Toll Like Receptors in the Intestine are altered in HIV disease ............................ 68 Summary ............................................................................................................................. 69 Introduction ......................................................................................................................... 71 Results ................................................................................................................................. 74 TLR expression is increased and TLR location modified in the epithelium and lamina propria of Viremic HIV+ patients .......................................................................................... 74 Recovery of TLR 4 and TLR 9 expression in the Immune Success Population; Toxicity of ART for epithelial TLR3 Expression ................................................................................ 82 Elevated TLR expression during a Failure to reconstitute immune homeostasis ............ 85 Inflammation and H&E staining ..................................................................................... 88 Discussion ........................................................................................................................... 90 Materials and Methods ........................................................................................................ 94 Patient Data ..................................................................................................................... 94 Immunofluorescence ....................................................................................................... 96 Metamorph ...................................................................................................................... 97 Statistics........................................................................................................................... 98 vii Chapter 4: Discussion ............................................................................................................ 100 Summary of Findings ........................................................................................................ 101 Discussion ......................................................................................................................... 105 Future Directions ............................................................................................................... 108 Confirm TLR expression alterations in Colonic Epithelium of HIV (+) and HIV (-) individuals using Flow cytometry. ....................................................................................... 108 TLR ligands and cytokines alter the abundance and localization of TLRs on the colonic epithelium and lamina propria ............................................................................................
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