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2.2.1 HIV-1 Subtypes 18 REFERENCE ONLY UNIVERSITY OF LONDON THESIS Degree fV \o Year fLoo^ Name of Author S C O PYR IG H T This is a thesis accepted for a Higher Degree of the University of London. It is an unpublished typescript and the copyright is held by the author. All persons consulting the thesis must read and abide by the Copyright Declaration below. COPYRIGHT DECLARATION I recognise that the copyright of the above-described thesis rests with the author and that no quotation from it or information derived from it may be published without the prior written consent of the author. LOANS Theses may not be lent to individuals, but the Senate House Library may lend a copy to approved libraries within the United Kingdom, for consultation solely on the premises of those libraries. Application should be made to: Inter-Library Loans, Senate House Library, Senate House, Malet Street, London WC1E 7HU. 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C:\Documents and Settings\lproctor\Local Settings\Temporary Internet Files\OLK8\Copyright - thesis (2).doc Molecular Epidemiology of HIV-1 in the United Kingdom by Stephane Hue, M.Sc. Centre for Virology Royal Free and University College Medical School University College London Thesis submitted for the degree of Doctor in Philosophy February 2005 UMI Number: U593689 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U593689 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract HIV infection is now the fastest-growing serious health hazard in the United Kingdom (UK), with an estimated 53,000 infected adults at the end of 2003. Despite a recent increase in heterosexually acquired infections, the most prevalent clade of virus within the country remains subtype B, from the main group of HIV-1, which is mainly transmitted through sex between men. To date, very little is known about how subtype B successfully invaded the British population, and how the virus has subsequently spread and evolved. Given that molecular data on HIV-1 is becoming increasingly available since the introduction of routine gene sequencing for drug-resistance monitoring, the present thesis proposes to assess the reliability of the HIV-1pol gene for molecular analyses of epidemiological relevance. Identification of transmission networks by phylogenetic means were primarily conducted, with the further goal to investigate the dynamics of HIV-1 transmission at both individual and population level in the UK. Evolutionary and epidemiological approaches were then combined in order to assess the correlates of transmission within a population of primary HIV-1 infected individuals within a localised risk group, exploiting both molecular and clinical data. Finally, the epidemic history of HIV-1 subtype B in the UK was reconstructed from sampled HIV-1 pol gene sequences, providing new insights into the complexity of HIV- 1 epidemics that must be considered when developing monitoring and prevention initiatives. The analyses presented in these pages emphasizes the advantage of combining state-of-the-art epidemiological studies to phylogenetic frameworks when investigating the dynamics of a viral epidemic as complex as HIV-1. Acknowledgments The reasons to thank the persons I wish to thank are legion. In their own ways, they all provided me with unconditional support, trust and anxiety. Not only did this thesis blossom through contact with them, but I did too. I am first and foremost indebt to my supervisor Dr Deenan Pillay for his trust, aid and irony. I owe Dr Jonathan Clewley for his expertise, Dr Patricia Cane for her assistance. I owe Dr Paul Kellam and the Viral Genomic and Bioinformatics Group for their warmth and proficiency. I owe Dr Oliver Pybus and Dr Andy Rambaut for their insight. I owe many people at the University of Birmingham, Birmingham Heartlands Hospital, Central Health Protection Agency, Windeyer Institute of Medical Research and the sordid King & Queen for their generosity. I owe Catherine Gale for her kind-hearted altruism. I owe my friends for their praiseworthy patience and my family for the unreasonable faith they have in me. I owe Sarah Abraham for making me do it. Contributions to this Thesis Chapter lll-IV-V The HIV-1 pol gene used in this thesis were extracted, amplified and sequenced by Judith Workman and Daina Ratcliffe at the Health Protection Agency Antiviral Susceptibility Reference Unit, Birmingham Heartlands Hospital, Birmingham, UK. Chapter IV Dr David Pao, Dr Martin Fischer and Dr Gillian Dean from the Department of GU Medicine, Brighton and Sussex University Hospitals, Brighton, UK, recruited the study cohort and collected clinical data for each patient. Professor Caroline Sabin from the Department of Primary Care and Population Sciences, Royal free & University College Medical School, London, UK performed all statistical analyses. Chapter V The sequences used for the estimation of the HIV-1 subtype B pol gene evolutionary rate were generated by the Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Dr Oliver Pybus and Dr Andrew Rambaut provided assistance in the implementation of the methods described in this chapter and contributed to the interpretation of the results. Contents Abstract II Acknowledgements iii Contribution to this Thesis iv Contents V Figures ix Tables xi Chapter 1: A Biased Introduction to HIV-1 1 1 Human Immunodeficiency Virus & AIDS 1 1.1 Organisation of HIV-1 2 1.2 HIV-1 Replication Cycle 3 1.2.1 Early Phase of Replication 5 1.2.2 Late Phase of Replication 7 1.3 Course of HIV-1 Infection 9 1.3.1 Primary Infection 9 1.3.2 Chronic Asymptomatic Infection 10 1.3.3 Clinical AIDS 11 2 Mechanisms of HIV-1 Variation 11 2.1 Causes of HIV-1 Evolution 12 v 2.1.1 Mutations 12 2.1.2 Recombination 13 2.1.3 Selection 15 2.2 Consequences of HIV-1 Evolution 18 2.2.1 HIV-1 subtypes 18 2.2.2 Drug Resistance 20 3 Epidemiology of HIV-1 21 3.1 HIV-1 in the United Kingdom 22 3.2 Molecular Epidemiology of HIV-1 24 3.2.1 Controversial Origin of HIV-1 26 3.2.2 The Florida Dentist Case and Followers 27 4 The Present Thesis 29 Chapter II: Methods and Principles 31 1 Study Population: The ASRU pol Database 31 1.1 Specimen Collection 31 1.2 Ethics Committee Approval & Patient Consent 32 2 Bench Wbrk 32 2.1 Extraction of HIV-1 RNAfrom Blood Samples 32 2.2 Reverse Transcription (RT) of HIV-1 RNA 33 2.3 Polymerase Chain Reaction (PCR) Amplification 33 2.4 cDNA Purification 35 2.5 Agarose Gel Electrophoresis 36 2.6 Sequencing 36 2.7 Subtyping & Drug Resistance Testing 37 3 Molecular Phylogenetics 38 3.1 Sequence Alignments 39 3.2 Phylogenetic Trees 41 vi 3.3 Phylogenetic Methods 43 3.4 Models of Molecular Evolution 51 3.5 Robustness and bootstrapping 56 4 Population Dynamics 57 4.1 Neutral Theory of Evolution & the Molecular Clock 57 4.2 Population Dynamics & The Coalescent 58 Chapter III: Identification of True Linkages on the Basis of thepol Gene Variability 63 1 Introduction 63 2 Matherial & Methods 65 2.1 Study Cohort 65 2.2 Gene Amplification & Sequencing 66 2.3 Genetic Distances 66 2.4 Phylogenetic Reconstruction 67 2.5 Sequence Data 69 3 Results 70 4 Discussion 79 Chapter IV: Correlates of Sexual Risk and HIV-1 Transmission during Primary Infection 82 1 Introduction 82 2 Material & Methods 84 2.1 Study Cohort 84 2.2 Epidemiological & Clinical Data 85 2.3 Statistical Analyses 86 2.4 Recombination Analyses 87 3 Results 89 3.1 Epidemiological Data 89 vii 3.2 Phylogenetic analyses 91 3.3 Statistical Analyses 91 3.4 Recombination Analyses 94 4 Discussion 96 Chapter V: Epidemic History and Dynamics of HIV-1 Subtype B in the United Kingdom 103 1 Introduction 103 2 Material & Methods 105 2.1 Study Population 105 2.2 Phylogenetic reconstruction 105 2.3 Estimation of HIV-1 Subtype B pol Gene Rate of Evolution 106 2.4 Demographic History & Population Dynamics 108 3 Results 111 3.1 Introduction of HIV-1 Subtype B in the UK 111 3.2 Estimation of HIV-1 Subtype B pol Gene Rate of Evolution 112 3.3 Demographic History & Parameter Estimation 115 4 Discussion 120 Chapter VI: General Discussion 124 1 Violated Assumptions 125 2 Selection Bias 126 3 Recombination 127 4 Who's Next? 129 Bibliography 131 Appendix 192 viii Figures Chapter 1 1 Fig.
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