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UNIVERSITY of CALIFORNIA, MERCED Purification and Study Of UNIVERSITY OF CALIFORNIA, MERCED Purification and Study of CC Chemokine-Based Strategies to Combat Chronic Inflammation and HIV A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Quantitative and Systems Biology by Anna Faith Nguyen, B.S., University of California, Davis Committee in charge: Professor Michael Cleary, Chair of Advisory Committee Professor Andy LiWang Professor Patricia J. LiWang, Supervisor Professor Maria Zoghbi 2017 Copyright Anna Faith Nguyen, 2017 All Rights Reserved The dissertation of Anna Faith Nguyen, titled, “Purification and Study of CC Chemokine- Based Strategies to Combat Chronic Inflammation and HIV”, is approved, and is acceptable ion quality and form for publication on microfilm and electronically: _________________________________ Date _______________ Professor Andy LiWang _________________________________ Date _______________ Professor Maria Zoghbi Supervisor _________________________________ Date _______________ Professor Patricia J. LiWang Chair _________________________________ Date _______________ Professor Michael Cleary University of California, Merced 2017 iii To my friends, family, and especially husband. I love you all so much; thank you for your endless support and patience. And Marko, thank you for not popping out too soon. iv Table of Contents I. List of Figures………...…………………………………………………………….…vii II. List of Tables…………………………………………………………………………..x III. List of Abbreviations……………………………………………………..………….xi IV. Acknowledgements...………………………………..…………………………….xiii V. Vita for Anna Faith Nguyen………………………………………………...….......xiv VI. Abstract……………………………………………………………………..………,xv Chapter 1. Introduction…………………………………………………………………….….1 1.1 Introduction to CC Chemokines……………………………………………….….1 1.2 The Role of CC Chemokines in Chronic Inflammation……………………….7 1.3 The Role of CC Chemokines in HIV Infection…………………………….…….10 1.3.2 HIV Entry into Human Cells……………………………………….……10 1.3.2 HIV Latency in Human Cells…………………………………………...14 Chapter 2. Biophysical and Computational Studies of the vCCI:vMIP-II complex…17 2.1 Introduction………………………………………………………………...…..…..17 2.2 Materials and Methods…………………………………………………………...19 2.2.1 Protein Purification……………………………………………………19 2.2.2 NMR Spectroscopy…………………………………………………….23 2.2.3 Isothermal Titration Calorimetry (ITC)………………………………27 2.2.4 Fluorescence Anisotropy…………………………………………….29 2.2.5 Molecular Dynamics……………………………………………………30 2.2.6 Figure Preparation……………………………………………………31 2.3 Results……………………………………………………………………………...31 2.3.1 Folded vCCI can be produced from E. coli……………….………….31 2.3.2 vCCI:vMIP-II produce a high affinity complex………………………..34 2.3.3 Changes in chemical shift suggest vCCI:vMIP-II interaction is similar to other vCCI:chemokine complexes…………………………………….….35 2.3.4 Molecular Dynamics simulations on vCCI:vMIP-II…………………37 2.4 Discussion………………………………………………………...………...…..…44 Chapter 3. The effect of N-terminal cyclization on the function of the HIV entry inhibitor 5P12 RANTES……………………………………..………………………………..47 3.1 Introduction………………………………….……………………………………47 3.2 Materials and Methods…………………………………….…………………..…49 3.2.1 Protein Purification…………………………………………………..…49 3.2.2 Obtaining rates of 5P12-RANTES and 5P12-RANTES-Q0E Cyclization……………………………………………………………........…..50 3.2.3 NMR Spectroscopy……………………….……………………………51 3.2.4 Quantifying N-terminal Cyclization………………………….……..…51 3.2.5 Cell Lines and Viruses……………………………………………….…52 3.2.6 Single Round Pseudovirus Production…………………………….…52 3.2.7 Single-Round Pseudoviral Assay……………………………………..52 3.2.8 CCR5 Functional Assays in CHO-K1 cells…………………………...53 3.2.9 CCR5 Activity in HeLa-P5L………………………………………….…54 3.3 Results…………………………………………………………………………...…55 3.3.1 5P12-RANTES N-terminal cyclization………………………………..55 3.3.2 5P12-Q0E also cyclizes to produce mature 5P12-RANTES……..…57 v 3.3.3 High potency HIV inhibition does not require N-terminal cyclization or N-terminal glutamine…………………….……………………………………58 3.3.4 The effect of the N-terminal amino acid and its state of cyclization on activation CCR5………………………………….……………………………61 3.4 Discussion………………………………………………………...………………..62 Chapter 4: Preliminary Results of Next Generation Chimeric 5P12-Linker-C Peptide HIV Entry Inhibitors………………………………………………………………………....65 4.1 Introduction…………..…………………………………….…………………..…65 4.2 Methods and Results……………………………………….……………….…68 4.2.1 1 Expression and Purification of 5P12-Linker-T1144 and 5P12- Linker-T-2635……………………………………………………………...…..68 4.2.2 NMR Spectroscopy of 5P12-Linker-T1144 and 5P12-Linker- T2635……………………………………………………………………....…..69 4.2.3 Preliminary Pseudoviral Assays comparing 5P12-Linker-T1144 and 5P12-Linker-T-2635 with 5P12-Linker-C37………………….....…….....70 4.2.4 Preliminary Pseudoviral Assays comparing 5P12-Linker-T1144 and 5P12-Linker-T-2635 with 5P12-Linker-C37 with C37-Resistant gp41 Mutants…………………………………………………………………………73 4.3 Discussion and Future Directions…………………………………….……..…75 Chapter 5. Design and Purification of a CC Chemokine-Based Activator of HIV Latency………………………………………………………………………………………….77 5.1 Introduction…………………………………..…………………...………………..77 5.2 Methods and Results………………………………….…………………..………81 5.2.1 Design and Purification of 5P14-Linker-Tat………………………..…81 5.2.2 NMR Spectroscopy off 5P14-Linker-Tat…………………………...…87 5.2.3 Preliminary Results for HIV LTR Activation Assay………………..…88 5.3 Discussion and Future Directions……………………………...……………...…90 Chapter 6: Conclusions and Future Directions………………………………………..…92 VII. References……………………………………...………………………………....96 Appendix A: Supplementary Information for Chapter 2……………………………….120 Appendix B: Supplementary Information for Chapter 3……………………………….127 Appendix C: Supplementary Information for Chapter 4………………………………129 vi I. List of Figures Chapter 1 Figures: Figure 1.1: Leukocyte Chemotaxis due to Chemokine Gradient……………………….......2 Figure 1.2: CC Chemokine Receptors and their CC Chemokine Ligands…………………4 Figure 1.3: Structures of CC Chemokines and Receptors…………………………....………6 Figure 1.4: The Rabbitpox Viral CC Chemokine Inhibitor Protein…………………....……..9 Figure 1.5: HIV Entry into the Cell…………………………………………………..…………11 Figure 1.6: Sequence Comparison of Wild Type RANTES/CCL5 and the Variant 5P12- RANTES…………………………………………………………………………………………12 Figure 1.7: HIV Latency and Shock and Kill Method…………………………………..…….15 Chapter 2 Figures: Figure 2.1: Comparison of unbound vCCI produced in yeast and E. coli…………..………21 Figure 2.2: vCCI:vMIP-II starting point for MD simulations…………………………...….…31 Figure 2.3: Bound Versus Unbound vCCI and vMIP-II Spectra………………………….…33 Figure 2.4: Competition Fluorescence Anisotropy of the vCCI:vMIP-II Interaction..…..…34 Figure 2.5: Changes in chemical shift upon vCCI:vMIP-II complex formation……..……...36 Figure 2.6: Complexes after 1 µsec molecular dynamics simulation of vCCI:chemokine variants……………………………………………………………………………………….....38 Figure 2.7: Secondary structure changes of the vCCI:Chemokine variants complex throughout the MD trajectory………………………………………………………………......39 Figure 2.8: Root mean square fluctuation values for vCCI:Chemokine Variant complexes……………………………………………………………………………………….40 Figure 2.9: Interstrand H-Bonds between vCCI and chemokine variants throughout MD trajectory…………………………………………………………………………………………40 Figure 2.10: Occlusion Maps for vCCI with vMIP-II or MIP-1β…………………………..…42 Figure 2.11: Interactions between vCCI and vMIP-II or MIP-1β…………………………....43 Figure 2.12: Interactions illuminated by molecular dynamics simulation of the vCCI:MIP- 1β and vCCI:vMIP-II complex……………………………………………………………….…46 Chapter 3 Figures: Figure 3.1: Cyclization reactions of N-terminal glutamine and glutamate residues in a polypeptide chain……………………………………………………………………….…..…..48 vii Figure 3.2: HSQC spectra of 15N-labeled Q0E, after varying incubation conditions….…50 Figure 3.3: Uncyclized 5P12-RANTES………………………………………………...……..55 Figure 3.4: 5P12-RANTES cyclization……………………………………………...………...56 Figure 3.5: 5P12-RANTES-Q0E………………………………………………………………57 Figure 3.6: Cyclized 5P12-RANTES-Q0E……………………………………………...….…58 Figure 3.7: Other 5P12-RANTES N-terminal Mutant Controls………………………..…....60 Figure 3.8: Calcium Flux in CHO-K1 cells induced with RANTES variants…………......…61 Chapter 4 Figures: Figure 4.1: 5P12-Linker-C37 inhibiting CCR5- or CXCR4-utilizing strains of HIV…..…....67 Figure 4.2: Sequence comparison of C-peptide analogs with C Heptad Repeat of HIV....68 Figure 4.3: Figure 4.3: HSQC NMR of 5P12-Linker-T1144 and 5P12-Linker-T2635…….70 Figure 4.4: Comparison of Preliminary IC50 values of 5P12-Linker Variants with various viruses…………………………………………………………………………………..……….73 Figure 4.5: NL4-3 and PVO.4 with locations of resistance/sensitivity mutations from Table 4.2 highlighted…………………………………………………………………..……………....74 Figure 4.6: Preliminary IC50 Values of 5P12-Linker variants with PVO.4-derived gp41 Sensitivity Mutants…………………………………………………………………………...…75 Chapter 5 Figures: Figure 5.1: Designs for a Chemokine Receptor-Targeting HIV Latency Abstractor……..78 Figure 5.2: Bound and unbound structures of HIV Tat……………………………………..80 Figure 5.3: General overview of the purification of 5P14-Linker-Tat……………………….82 Figure 5.4: HSQC NMR spectrum of 5P14-Linker-Tat……………………………………....88 Figure 5.5: Preliminary results of HeLa TZM-bl β-Galactosidase transcription activation due to 5P14-Linker-Tat………………………………………………………………………...89 Appendix A Figures: Figure A-1: Overview of protein design of vCCI used in Chapter 2……………………..…120 Figure A-2: Overview of the Purification of vCCI……………………………………………121 Figure A-3: Overview
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