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Within-Host Evolution of Hiv-1: Novel Pathways of Virus Escape from Cellular and Humoral Immunity

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Within-Host Evolution of Hiv-1: Novel Pathways of Virus Escape from Cellular and Humoral Immunity University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Within-Host Evolution Of Hiv-1: Novel Pathways Of Virus Escape From Cellular And Humoral Immunity Edward Kreider University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Microbiology Commons Recommended Citation Kreider, Edward, "Within-Host Evolution Of Hiv-1: Novel Pathways Of Virus Escape From Cellular And Humoral Immunity" (2016). Publicly Accessible Penn Dissertations. 2406. https://repository.upenn.edu/edissertations/2406 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2406 For more information, please contact [email protected]. Within-Host Evolution Of Hiv-1: Novel Pathways Of Virus Escape From Cellular And Humoral Immunity Abstract Longitudinal HIV-1 single genome sequencing (SGS), which permits unambiguous genetic characterization of circulating viral strains without introduction of PCR error, can be used to identify sites in the viral genome that are under selective pressure. Following transmission, the earliest sites under positive selection often fall in cytotoxic T lymphocyte (CTL) epitopes. During escape from CTL immune pressure, viral sequences typically exhibit nonsynonymous mutations within the span of the cognate T cell epitope. I applied SGS to study sequence evolution in the HIV-1 5’ leader sequence, which is thought to be translationally silent. I observed mutational patterns consistent with CTL escape and demonstrated that the HIV-1 5’ leader expresses T cell antigens from non-canonical one-off AUG codons (e.g. CUG). While these non-canonical start codons can be mutated during CTL escape, a reverse transcriptase overextension error periodically restores a one-off AUG within the 5’ leader. As infection ensues, sites under selection within the gene encoding the viral envelope glycoprotein (Env) often fall within autologous neutralizing antibody epitopes. In a subset of individuals, the strain-specific neutralizing antibody response develops into a broadly cross-reactive neutralizing antibody (bnAb) response. To understand what factors influence bnAb ontogeny, I used SGS to study Env evolution both during natural infection and immunotherapy. I found viral diversification in bnAb contact esiduesr and divergence of the virus population into multiple persistent lineages to precede bnAb development. Taken together, these data demonstrate that longitudinal HIV-1 SGS can be used to discover novel aspects of virus biology and host- pathogen interactions. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Beatrice H. Hahn Subject Categories Microbiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2406 WITHIN-HOST EVOLUTION OF HIV-1: NOVEL PATHWAYS OF VIRUS ESCAPE FROM CELLULAR AND HUMORAL IMMUNITY Edward F. Kreider A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2016 Supervisor of Dissertation ____ ____________________ Dr. Beatrice H. Hahn, MD Professor, Departments of Medicine and Microbiology Graduate Group Chairperson ________________________ Dr. Daniel S. Kessler, PhD Associate Professor of Cell and Developmental Biology Dissertation Committee James A. Hoxie, MD (Chair), Professor, Department of Medicine Robert W. Doms, MD, PhD, Professor, Department of Pathology and Laboratory Medicine Scott E. Hensley, PhD, Associate Professor, The Wistar Institute Rahul M. Kohli, MD, PhD, Assistant Professor, Department of Medicine ACKNOWLEDGMENTS I would first and foremost like to thank my mentor, Dr. Beatrice Hahn. She has helped me flourish as a scientist and provided me with unbelievable opportunities. Her mentorship over the past four years has molded me as a both a person and an investigator. I cannot thank her enough. Dr. George Shaw has also played an integral role both in my training and mentorship. His insistence that we understand every stripe in every highlighter plot forced me to think critically about every datum and even led to unexpected discoveries. My thesis committee members Dr. James Hoxie, Dr. Robert Doms, Dr. Rahul Kohli, and Dr. Scott Hensley have all provided me with guidance and mentorship on personal, academic, and scientific matters. Dr. Doms is a major reason why I am here today and I am so thankful for the guidance and opportunities he has provided me. Dr. Yingying Li welcomed me to the lab, taught me everything that I know about sequencing, and cared for me every day of my PhD training. Dr. Hui Li is an incredible collaborator and friend whose door was always open. Dr. Gerald Learn provided me with a foundation in sequence analysis and is a treasured colleague. Dr. Katherine Bar was a mentor and, to my great pleasure, a collaborator. To the Hahn lab graduate students who have been a family throughout these past four years, in particular Hannah Barbian and Shilpa Iyer, thank you so much for being there. And Ranjit Warrier, whose calming presence got me through tough days. Additionally, many thanks are due to all of the collaborators who welcomed me into their labs: Dr. Persephone Borrow, Dr. Andrew McMichael, and Dr. Bette Korber. As well to the CHAVI Duke family, particularly Dr. Barton Haynes and Dr. Mattia Bonsignori I also need to thank my social support network: Liz, Sarah, Andrew, Alice, Justin, and my entire MSTP class, and Skip, Maggie, and Maureen. Finally, to my family and Fraz, thank you for putting up with me. ii ABSTRACT WITHIN-HOST EVOLUTION OF HIV-1: NOVEL PATHWAYS OF VIRUS ESCAPE FROM CELLULAR AND HUMORAL IMMUNITY Edward F. Kreider Beatrice H. Hahn, MD Longitudinal HIV-1 single genome sequencing (SGS), which permits unambiguous genetic characterization of circulating viral strains without introduction of PCR error, can be used to identify sites in the viral genome that are under selective pressure. Following transmission, the earliest sites under positive selection often fall in cytotoxic T lymphocyte (CTL) epitopes. During escape from CTL immune pressure, viral sequences typically exhibit nonsynonymous mutations within the span of the cognate T cell epitope. I applied SGS to study sequence evolution in the HIV-1 5’ leader sequence, which is thought to be translationally silent. I observed mutational patterns consistent with CTL escape and demonstrated that the HIV-1 5’ leader expresses T cell antigens from non-canonical one-off AUG codons ( e.g. CUG). While these non-canonical start codons can be mutated during CTL escape, a reverse transcriptase overextension error periodically restores a one-off AUG within the 5’ leader. As infection ensues, sites under selection within the gene encoding the viral envelope glycoprotein (Env) often fall within autologous neutralizing antibody epitopes. In a subset of individuals, the strain-specific iii neutralizing antibody response develops into a broadly cross-reactive neutralizing antibody (bnAb) response. To understand what factors influence bnAb ontogeny, I used SGS to study Env evolution both during natural infection and immunotherapy. I found viral diversification in bnAb contact residues and divergence of the virus population into multiple persistent lineages to precede bnAb development. Taken together, these data demonstrate that longitudinal HIV-1 SGS can be used to discover novel aspects of virus biology and host-pathogen interactions. iv TABLE OF CONTENTS ACKNOWLEDGMENTS ........................................................................................................ ii ABSTRACT ................................................................................................................................ iii List of Tables ............................................................................................................................. viii List of Illustrations ...................................................................................................................... ix CHAPTER 1 .................................................................................................................................. 1 Section 1.1 – AIDS and HIV-1 .......................................................................................................... 2 Section 1.2 – Biology of the 5’ leader sequence ....................................................................... 3 Section 1.3 –HIV-1 evolution and the T cell response ........................................................... 8 Section 1.4 – HIV-1 and the neutralizing antibody response ........................................... 13 Section 1.5 – Monoclonal bnAbs in prevention and therapy ........................................... 18 Section 1.6 – References ................................................................................................................ 20 Section 1.7 – Figures ....................................................................................................................... 35 CHAPTER 2 ................................................................................................................................ 43 Section 2.1 – Abstract ..................................................................................................................... 45 Section 2.2 – Introduction ...........................................................................................................
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