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Fighting Hiv Infection by Defining Mechanisms to Remodel Semen-Derived

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Fighting Hiv Infection by Defining Mechanisms to Remodel Semen-Derived University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2015 Fighting HIV Infection by Defining Mechanisms ot Remodel Semen-Derived Amyloid Fibrils Laura Castellano University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biochemistry Commons, Pharmacology Commons, and the Virology Commons Recommended Citation Castellano, Laura, "Fighting HIV Infection by Defining Mechanisms ot Remodel Semen-Derived Amyloid Fibrils" (2015). Publicly Accessible Penn Dissertations. 1024. https://repository.upenn.edu/edissertations/1024 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1024 For more information, please contact [email protected]. Fighting HIV Infection by Defining Mechanisms ot Remodel Semen-Derived Amyloid Fibrils Abstract Human immunodeficiency virus (HIV) is a major public health threat worldwide, with 80% of infections acquired through sexual transmission. Semen is the principal vector for the transmission of HIV and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2), assemble into amyloid fibrils that promote HIV infection. Semen-derived amyloid fibrils enhance infectivity by capturing HIV virions and facilitating their attachment and fusion to target cells. Deciphering methods to dissolve seminal amyloid fibrils would provide a novel preventative strategy for reducing HIV infection via sexual transmission. Three previously described anti-amyloid agents were used to disassemble and/or counteract seminal amyloid fibrils: 1) Hsp104, an amyloid-remodeling factor from yeast, 2) CLR01, a lysine-specific molecular tweezer, and 3) EGCG, a small molecule polyphenol from green tea. Each strategy was found to antagonize seminal amyloid activity through diverse mechanisms. For instance, Hsp104 and a potentiated Hsp104 variant, Hsp104A503V, remodeled seminal amyloid fibrils into non-fibrillar aggregates and catalytically inactive Hsp104 scaffolds clustered fibrils into larger assemblies. Additionally, Hsp104 was modified ot interact with the chambered protease ClpP, to enable coupled remodeling and degradation of seminal amyloid. CLR01 remodeled pre-formed amyloid fibrils through disruption of critical lysine residues, neutralized the cationic fibril surface charge, and exhibited a direct anti-viral effect via disruption of the viral membrane. Finally, epigallocatechin gallate (EGCG) is the first small molecule that can eradicate all four classes of seminal amyloid. Thus, all three strategies were highly effective at antagonizing seminal amyloid fibrils and could have therapeutic utility. Altogether, these findings provide insight into developing microbicidal agents that can abolish the infection-enhancing capabilities of seminal amyloid and counter HIV transmission. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Pharmacology First Advisor James Shorter Keywords amyloid fibrils, HIV, Hsp104, SEVI, small molcules Subject Categories Biochemistry | Pharmacology | Virology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/1024 FIGHTING HIV INFECTION BY DEFINING MECHANISMS TO REMODEL SEMEN-DERIVED AMYLOID FIBRILS Laura M. Castellano A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2015 Supervisor of Dissertation _______________________ James Shorter, Ph.D., Associate Professor of Biochemistry and Biophysics Graduate Group Chairperson ________________________ Julie Blendy, Ph.D. Professor of Pharmacology Dissertation Committee Rahul Kohli, M.D., Ph.D., Assistant Professor of Medicine Mark Lemmon, Ph.D., Professor of Biochemistry and Biophysics Michael Marks, Ph.D., Professor of Pathology and Laboratory Medicine Kelly Jordan-Sciutto, Ph.D., Professor of Pathology FIGHTING HIV INFECTION BY DEFINING MECHANISMS TO REMODEL SEMEN-DERIVED AMYLOID FIBRILS COPYRIGHT 2015 Laura M. Castellano This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit http://creativecommons.org/licenses/by-ny-sa/2. ACKNOWLEDGMENT I have many people to thank for their guidance and support throughout the course of my graduate work. First, I need to thank all Shorter Lab members, past and present, for providing a great work environment: Jim – for providing me with mentorship and direction throughout my project and helping me grow as a scientist; Morgan and Liz – for teaching me a great deal about designing experiments and learning new techniques in the lab; Mariana – for always lending an ear and providing advice on science and life; Alice – for her constant reassurance and friendship; and Mike (my “lab husband”) – for being a great colleague and a close friend through good times and bad. I also need to thank Weissman Lab members, especially Veronica, for their help setting up HIV infectivity assays and allowing me to use their lab space and our collaborators in the Munch lab that contributed many useful virological experiments in this thesis. I also need to recognize the National Science Foundation Graduate Research Fellowship for funding my graduate work. I would also like to acknowledge my family for their constant support. I met my (real) husband, Nick, during my first year at Penn, and I cannot imagine what it would have been like to go through the challenges of graduate school without him. I also need to thank my parents for shaping me to be the person I am today and for their continual encouragement throughout my life. iii ABSTRACT FIGHTING HIV INFECTION BY DEFINING MECHANISMS TO REMODEL SEMEN-DERIVED AMYLOID FIBRILS Laura M. Castellano Dr. James Shorter Human immunodeficiency virus (HIV) is a major public health threat worldwide, with 80% of infections acquired through sexual transmission. Semen is the principal vector for the transmission of HIV and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2), assemble into amyloid fibrils that promote HIV infection. Semen-derived amyloid fibrils enhance infectivity by capturing HIV virions and facilitating their attachment and fusion to target cells. Deciphering methods to dissolve seminal amyloid fibrils would provide a novel preventative strategy for reducing HIV infection via sexual transmission. Three previously described anti-amyloid agents were used to disassemble and/or counteract seminal amyloid fibrils: 1) Hsp104, an amyloid-remodeling factor from yeast, 2) CLR01, a lysine- specific molecular tweezer, and 3) EGCG, a small molecule polyphenol from green tea. Each strategy was found to antagonize seminal amyloid activity through diverse mechanisms. For instance, Hsp104 and a potentiated Hsp104 variant, Hsp104A503V, remodeled seminal amyloid fibrils into non-fibrillar aggregates and catalytically inactive Hsp104 scaffolds clustered fibrils into larger assemblies. Additionally, Hsp104 was modified to interact with the chambered protease ClpP, to enable coupled remodeling and degradation of seminal amyloid. CLR01 remodeled pre- formed amyloid fibrils through disruption of critical lysine residues, neutralized the cationic fibril surface charge, and exhibited a direct anti-viral effect via disruption of the viral membrane. Finally, epigallocatechin gallate (EGCG) is the first small molecule that can eradicate all four iv classes of seminal amyloid. Thus, all three strategies were highly effective at antagonizing seminal amyloid fibrils and could have therapeutic utility. Altogether, these findings provide insight into developing microbicidal agents that can abolish the infection-enhancing capabilities of seminal amyloid and counter HIV transmission. v TABLE OF CONTENTS ACKNOWLEDGMENT ………………………………………………………………...………III ABSTRACT…….. ............................................................................................................ IV LIST OF TABLES ............................................................................................................ IX LIST OF ILLUSTRATIONS .............................................................................................. X CHAPTER 1: BACKGROUND AND SIGNIFICANCE ..................................................... 1 1.1 Discovery of natural agents involved in HIV transmission ................................................. 1 1.2 How does SEVI augment HIV infection? ............................................................................... 3 1.3 PAP85 and SEM amyloid fibrils ............................................................................................. 6 1.4 A physiological role for semen-derived amyloid fibrils? .................................................... 8 1.5 Current strategies to counteract amyloid-mediated enhancement of HIV infection ...... 10 1.6 Amyloid strains ..................................................................................................................... 14 1.7 Established amyloid-remodeling factors ............................................................................ 17 1.7.1 Hsp104 ......................................................................................................................... 17 1.7.2 CLR01 ..........................................................................................................................
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