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In Presenting This Thesis Or Dissertation As a Partial Fulfillment Distribution Agreement In presenting this thesis or dissertation as a partial fulfillment of the requirements for an advanced degree from Emory University, I hereby grant to Emory University and its agents the non-exclusive license to archive, make accessible, and display my thesis or dissertation in whole or in part in all forms of media, now or hereafter known, including display on the world wide web. I understand that I may select some access restrictions as part of the online submission of this thesis or dissertation. I retain all ownership rights to the copyright of the thesis or dissertation. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. Signature: ____________________________________ _________________ Jung Hwa Kirschman Date The Role of Host Factors in HIV-1 Entry and Assembly By Jung Hwa Kirschman Doctor of Philosophy Graduate Division of Biological and Biomedical Science Immunology and Molecular Pathogenesis ________________________________ ________________________________ Gregory Melikian, Ph.D. Eric Hunter, Ph.D Advisor Committee Member ________________________________ ________________________________ Daniel Kalman, Ph.D. Baek Kim, Ph.D Committee Member Committee Member ________________________________ Anice Lowen, Ph.D. Committee Member Accepted: __________________________________________ Lisa A. Tedesco, Ph.D. Dean of the James T. Laney School of Graduate Studies ___________________ Date The Role of Host Factors in HIV-1 Entry and Assembly By Jung Hwa Kirschman M.S., Seoul National University, 2010 Advisor Gregory Melikian, Ph.D. An abstract of A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Division of Biological and Biomedical Sciences in Immunology and Molecular Pathogenesis 2018 Abstract The Role of Host Factors in HIV-1 Assembly and Entry By Jung Hwa Kirschman HIV-1 is a global health threat with no vaccine available. Current treatment regiments are generally effective, but life-long administration of antiretroviral drugs has side effects and is quite costly. Uncovering the molecular mechanisms underlying the HIV-1 life cycle is important for developing effective drugs. HIV-1 Env is the only viral surface protein and it functions by initiating fusion to the host cell membrane, thereby initiating infection. Env is a major target for neutralizing antibodies. However, due to a dense glycan shield covering the Env and complex conformational changes during the fusion process, access to Env neutralization epitopes is limited. We therefore examined how Env gets incorporated into virions and how it induces viral fusion with the host membrane. To incorporate into progeny virions, Env must be transported to the virus assembly sites on the plasma membrane and interact with the assembling structural Gag protein. Here we elucidated the role of Rab11 and FIP1C in Env trafficking during HIV-1 assembly (Chapter 2). We found that the C-terminal fragment of FIP1C, when expressed in cells, can sequester Env inside the endosomal recycling compartment and thereby block the Env incorporation into virions. This dominant negative effect is likely proceeded by endocytosis of Env from the plasma membrane and is dependent on tyrosine motifs in the Env cytoplasmic tail. We also examined the mechanism of restriction of HIV-1 fusion by the new restriction factor SERINC5 (Chapter 3). SERINC5 incorporates into virions in the absence of Nef and potently inhibits fusion of sensitive, but not resistant HIV-1 variants. Our results revealed that both sensitive and resistant Env glycoproteins are functionally inactivated over time and that the inactivation rate is increased upon SERINC5 incorporation into virions. Mutations that stabilize or destabilize specific regions on Env did not reveal a specific Env conformation that could be targeted by SERINC5. However, a CD4 mimetic compound accelerated SERINC5-mediated Env inactivation, while a conformational blocker that stabilizes a native Env structure delayed the functional inactivation of Env in the presence of SERINC5. Collectively, our studies provided new insights into the molecular mechanisms of HIV-1 interaction with the host proviral and restriction factors during virus assembly and entry into target cells. The Role of Host Factors in HIV-1 Entry and Assembly By Jung Hwa Kirschman M.S., Seoul National University, 2010 Advisor Gregory Melikian, Ph.D. A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Division of Biological and Biomedical Sciences in Immunology and Molecular Pathogenesis 2018 Acknowledgements I would like to thank: ♦Gregory Melikian, for his ideas and brilliant approach toward the second part of this project and his great passion toward mentorship and Science and for granting the great opportunity to be his student. Without his consistent support, this thesis literally could not be done. ♦Paul Spearman, for his ideas and foundations of the first part of this work. His passion and insights has been infused into the first part of the work. I appreciate for giving me opportunities to learn about HIV virology and to attend my first two Cold Spring Harbor Laboratory Retrovirus meetings. ♦Spearman Lab members: Lingmei Ding, Jason Hammonds (Mentor), Mingli Qi (Mentor), Xuemin Chen and Lena for technical and material contributions critical for the first part of work ♦Melikian Lab members: Mariana Marin (Mentor), Chetan Sood, Ashwanth Francis, Caleb Mason, Kenyanna Taylor for technical and theoretical contributions to the second part of work ♦My Thesis committee members: Daniel Kalman, Baek Kim, Eric Hunter, and Anice Lowen for additional ideas critical for this work. Especially big thanks to Dan for infinite support to get through multiple challenges as graduate student ♦Jonathan Kirschman, for being supportive husband and my cats Kunyang and Magu for offering lots of emotional support since I started my PhD. Table of Contents Chapter I: Introduction ....................................................................................................................... 1 Figures .............................................................................................................................................. 19 Fig 1. HIV-1 replication cycle…………………………………................................................................... 19 Fig 2. HIV-1 Env incorporation model................................................................................................. 20 Fig 3. HIV-1 Env CT …………………………................................................................................................. 21 References ....................................................................................................................................... 22 Chapter II: Dominant negative effect of C-terminal domain of FIP1C on HIV-1 Env ... 49 Abstract ........................................................................................................................................... 50 Introduction ................................................................................................................................... 51 Results .............................................................................................................................................. 64 Discussion ....................................................................................................................................... 62 Materials and Methods ............................................................................................................... 72 Figures ....................................................................................................................................................... 77 Fig. 1. Truncated FIP1C inhibits Env incorporation and particle infectivity...................... 77 Fig. 2. FIP1C560–649 sequesters Env in a perinuclear compartment in a CT-dependent manner.............................................................................................................................................................. 79 Fig. 3. Cell surface levels of CT144 Env and effect of FIP1C560–649 versus FIP2452–512...... 81 Fig. 4. Trapping of Env by GFP-FIP1C560–649 is dependent on specific trafficking motifs in the CT………………………………………………………………………………………………....................... 83 Fig. 5. Trapping of Env by GFP-FIP1C560–649 is dependent on specific trafficking motifs in the CT. ………………………………………………………............................................................................ 85 Fig. 6. Dominant-negative FIP1C560–649 fails to trap SIV Env in the ERC. ............................. 87 Fig 7. Dose titration of FIP1C560–649 and effects on SIVmac239 Env incorporation ........ 89 Fig 8. Particle infectivity correlates with replicative capacity ................................................ 91 Fig 9. Endosomal markers present in FIP1C560–649-positive ERC. .......................................... 93 Fig 10. Endocytosis and trapping of artificial Env in ERC ......................................................... 95 Fig 11. Model for Env trafficking and retention in ERC by truncated FIP1C…………....... 97 S1 Fig. Endocytosis and trapping of natural Env in ERC…........................................................
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