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Association Among Ccr5 Genotypes, Ccr5 Expression, and In ASSOCIATION AMONG CCR5 GENOTYPES, CCR5 EXPRESSION, AND IN VITRO HIV INFECTION Bangan John Submitted in partial fulfilment of the requirements For the degree of Master of Science Dissertation Advisor: Dr Peter A. Zimmerman Department of Biology CASE WESTERN RESERVE UNIVERSITY May, 2013 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Bangan John ______________________________________________________ Master of Science candidate for the ________________________________degree *. Roy Ritzmann (signed)_______________________________________________ (chair of the committee) Peter Zimmerman ________________________________________________ Christopher Cullis ________________________________________________ Daniel Tisch ________________________________________________ 12/20/2012 (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Dedication: I would like to dedicate this thesis to my family, the John’s. Table of Contents List of Tables ................................................................................................................. ii List of Figures .............................................................................................................. iii Acknowledgements ....................................................................................................... iv Abbreviations ................................................................................................................. v Abstract ......................................................................................................................... vi Chapter 1: Overview HIV infection, CCR5 chemokine receptors and CCR5 gene polymorphisms ............................................................................................................... 1 1.1 Introduction .......................................................................................................... 1 1.2 HIV-1: Infection and Tropism ............................................................................. 1 1.3 CCR5 receptor ..................................................................................................... 3 1.4 CCR5 Haplotype .................................................................................................. 6 1.5 CXCR4 receptor................................................................................................... 7 1.6 Antiretroviral therapy........................................................................................... 8 1.7 Host genetics ...................................................................................................... 10 1.8 Cell Biology: Human T Lymphocytes ............................................................... 11 Chapter 2: Rationale/Hypothesis and Method ............................................................. 14 2.1 Aims: .................................................................................................................. 15 2.2 Methodology ...................................................................................................... 16 2.2.1 Participants and Sample .............................................................................. 16 2.2.2 DNA Extraction and Polymerase Chain Reaction ...................................... 16 2.2.3 Ligase Detection Reaction-Fluorescent Microsphere Assay ...................... 17 2.2.4 Cells and Whole Blood Staining ................................................................. 17 2.2.5 FACS-based HIV fusion/Productive Infection Assay ................................ 18 2.2.5.1 Assay description [87] ............................................................................. 20 Chapter 3: Results and Discussion ............................................................................... 22 3.1 Genotyping: CCR5 genotypes from Human T lymphocytes ............................. 22 3.2 Phenotyping: CCR5 expression on T lymphocytes in relations to CCR5 Genotypes ................................................................................................................ 25 3.3 CCR5 Genotype and Infectivity of Human T lymphocytes ............................... 28 Chapter 4: Conclusion.................................................................................................. 31 4.1 Limitation and Future Directions ....................................................................... 33 Bibliography: ............................................................................................................... 34 i List of Tables Table 1. Six classes of ART and drugs ....................................................................... 10 Table 2. These are the channels and the antibodies that were used in the assays. ...... 21 Table 3. Number of individuals from various ethnicities............................................ 23 Table 4. CCR5 -2459 and Δ 32 allelic and genotypic frequencies ............................. 24 ii List of Figures Figure 1. General life cycle of HIV…………………………………………… 2 Figure 2. Chromosome 3 and location of the CCR5 gene…………………….. 3 Figure 3. Schematic overview of the viral strain, chemokine receptors and their ligands…………………………………………………………. 4 Figure 4. Schematic overview of the viral strain, chemokine receptors and their ligands…………………………………………………………. 8 Figure 5. Combination of Reporter virus system……………............................ 22 Figure 6. CCR5 expression on TCM with CCR5 genotypes…………………. 26 Figure 7. CCR5 expression on TCM with CCR5 genotypes………………….. 27 Figure 8. In vitro HIV infectivity in TCM with CCR5 genotypes…………….. 28 iii Acknowledgements I would like to thank my advisor, Dr Peter Zimmerman, who provided guidance and support for me throughout my studies. Also, I would like to acknowledge my committee members for their patience and guidance: Dr. Peter Zimmerman, Dr. Daniel Tisch, and Dr. Christopher Cullis. There are also people in the Zimmerman lab that I would like to thank, namely Dr. Rajeev Mehlotra – for his mentorship and advice, Melinda Blood, Dr. Scott Small, Akshaya Ramesh, Krufinta Bun, Tenisha Phipps, Barne Willie, Kyle Logue, and Cara Halldin. iv Abbreviations AfA African American AIDS Acquired Immunodeficiency Disease Syndrome ART Antiretroviral Therapy AsA Asian American CA Caucasian American CCR5 CC Chemokine Receptor 5 CXC CXC Chemokine CXCR4 CXC Chemokine Receptor 4 DNA Deoxyribonucleic Acid FMA Fluorescent Microsphere Array G/A Combination of nucleotide G and A G/G Combination of nucleotide G and G HA Hispanic American HAART Highly Active Antiretroviral Therapy HIV Human Immunodeficiency Virus IND India LDR Ligase Detection Reaction NK Natural Killer Cells NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors ORF Open Reading Frame PCR Polymerase Chain Reaction PNG Papua New Guinea R5 R5 variant of HIV RANTES Regulated in Activation Normal T Expressed and Secreted protein SNPs Single Nucleotide Polymorphisms TCM Central Memory T cell TEM Effector Memory T cells TEMRA Effector Memory T cells with marker protein - CD45RA TM Memory T cells TN Naïve T cells TTM Transitional Memory T cells UHC IRB University Hospital of Cleveland Institutional Review Board US-FDA United States of America Food and Drug Administration v Association Among CCR5 Genotypes, CCR5 Expression, and In Vitro HIV Infection Abstract BANGAN JOHN The single nucleotide polymorphisms (SNPs) in CCR5 (-2459 G>A [promoter], Δ32 deletion polymorphism [open reading frame, ORF]) influences the expression of CCR5 chemokine receptor on human T lymphocytes. CCR5 is a major coreceptor for HIV to bind to the T cell prior to fusion. Individuals have various frequencies of these polymorphisms, which influence their susceptible to HIV infection and disease progression. This thesis is focused on determining the association between these polymorphisms and CCR5 expression on T cells, as well as between these polymorphisms and in vitro HIV infection. The CCR5 -2459 genotype results that were obtained showed clear associations with CCR5 expression on the central memory T cell (TCM) subpopulation. That is, CCR5 -2459 G/G had lower levels of CCR5 expression as compared to A/A and G/A on the TCM cells. While with the CCR5 ORF genotypes, wildtype (Wt)/Δ32 had very low levels of CCR5 expression as compared to Wt/Wt. Furthermore, results obtained for CCR5 -2459 genotype and HIV infectivity of the TCM cells also clearly showed significant associations. These were observed when comparing CCR5 -2459 genotypes G/G and A/A (p=0.029), and also between G/A and G/G (p=0.049). That is, G/G had lower HIV infectivity of its TCM cells in comparison to those of both A/A and G/A genotypes. These findings, especially those of CCR5 -2459 G allele demonstrates its protective effect in the in vitro assay, thus, providing insights into expression and infection at the T cell subpopulation level. vi Chapter 1: Overview HIV infection, CCR5 chemokine receptors and CCR5 gene polymorphisms 1.1 Introduction Human immunodeficiency virus type (HIV) infection occurs when the virus gains entry into a host cell by first binding to the cell. For this to happen the host cell must have receptors expressed on its surface for the virus to bind to. These cell surface receptors include the primary receptor for HIV-1 infection, which is the cluster of differentiation 4 (CD4) and two specific chemokine coreceptors, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4
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