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Virus-Host Interaction: the Multifaceted Roles of Ifitms And

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Virus-Host Interaction: the Multifaceted Roles of Ifitms And Virus-Host Interaction: The Multifaceted Roles of IFITMs and LY6E in HIV Infection DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jingyou Yu Graduate Program in Comparative and Veterinary Medicine The Ohio State University 2018 Dissertation Committee: Shan-Lu Liu, MD, PhD, Advisor Patrick L. Green, PhD Jianrong Li, DVM., PhD Jesse J. Kwiek, PhD Copyrighted by Jingyou Yu 2018 Abstract With over 1.8 million newly infected people each year, the worldwide HIV-1 epidemic remains an imperative challenge for public health. Recent work has demonstrated that type I interferons (IFNs) efficiently suppress HIV infection through induction of hundreds of interferon stimulated genes (ISGs). These ISGs target distinct infection stages of invading pathogens and shape innate immunity. Among these, interferon induced transmembrane proteins (IFITMs) and lymphocyte antigen 6 complex, locus E (LY6E) have been shown to differentially modulate viral infections. However, their effects on HIV are not fully understood. In my thesis work, I provided evidence in Chapter 2 showing that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env), thereby inhibiting viral infection. IFITM proteins interacted with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions did not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes led to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appeared to be virus- strain dependent. Overall, this study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection. In Chapter three of this dissertation, I examined the effects of IFITMs on HIV-1 with different co-receptor tropism. I demonstrated that overexpression of IFITMs more dramatically suppressed ii entry of X4 (NL4.3 and HXB2) and dual tropic (89.6) viruses compared to their effect on R5 (JRFL and AD8) viruses, regardless of cell types. However, in all cases, the inhibition potency was ranked as IFITM3>IFITM2>IFITM1. Loss of function study revealed that knockdown IFITMs with short hairpin RNAs had modest effects on IFN-mediated viral entry compared to multi-round HIV-1 replication. Overall, this work suggests that IFITM proteins do not distinguish co-receptors CCR5 and CXCR4 to inhibit HIV-1 entry and that IFN-induced IFITMs mainly act in virus-producing cell to restrict HIV-1 replication. In Chapter four of this dissertation, I showed that LY6E promotes HIV-1 infection by enhancing viral entry and gene expression. Specifically, knockdown of LY6E in human PBMCs, SupT1, and THP-1 cells diminished HIV-1 replication. Virion-cell and cell-cell fusion experiments revealed that LY6E promotes membrane fusion of the viral entry step. Interestingly, I found that the LTR-driven HIV-1 gene expression was also enhanced by LY6E, suggesting additional roles of LY6E in HIV-1 replication. HIV-1 infection induced LY6E expression in human PBMCs, concomitant with increased production of type I IFN and some classical IFN-stimulated genes (ISGs). Altogether, these results demonstrate that IFN-inducible LY6E promotes HIV-1 entry and replication, highlighting a positive regulatory role of IFN-induced proteins in HIV-1 infection. In Chapter five of this dissertation, I showed that LY6E showed a distinct phenotype in low- CD4-expresisng Jurkat cells, i.e., LY6E inhibits HIV-1 entry by downregulating CD4. LY6E was found to be co-localized with CD4 on plasma membranes and further down-modulated CD4 on cell surface; this leads to compromised viral binding and subsequent viral entry. Ectopic expression of CD4 was able to rescue the phenotype of LY6E in Jurkat cells. The CD4 dependent inhibitory phenotype of LY6E can be recapitulated in low-CD4 primary cells human Monocyte- derived macrophages (MDMs). Taken together, this study reveals that LY6E likely modulates iii HIV-1 infection in a cell type dependent manner, and the CD4 surface expression level determines the sensitivity of HIV to LY6E. Overall, in this thesis work, I have investigated the role of IFITMs and LY6E in HIV-1 infection and discovered some multifaceted functions of these two families of proteins in modulating the different stages of the viral life cycle. My data highlight the more complex functions of type I IFNs and ISGs in HIV infection and AIDS pathogenesis. Information obtained in this thesis provides insights into understanding of the modes of action of type I IFNs and virus- host interaction in general, and could have therapeutic implications for prevention and treatment of HIV/AIDS. iv Dedication To my beloved parents Mr. Zhijia Yu and Mrs. Xuehua Tian, And my wonderful wife Mrs. Yawen Ni, Without whom none of my success would be achievable v Acknowledgements I would like to express my sincere gratitude to my advisor, Dr. Shan-Lu Liu, who had offered me such a great opportunity to work in his lab, to be educated in a land of freedom and democracy, and more importantly, in a kingdom of real and beautiful science. His hardworking, enthusiasm, and extraordinary insights into sciences have exerted profound influences on me and will be cherished for the rest of my life. I will never forget times that he sacrificed his nights and weekends to revise my presentation slides, manuscripts, and project outlines. His words “If you do not try, you will never know” will always inspire me along my scientific career. I would like to thank my committee members, Drs. Patrick Green, Jianrong Li, and Jesse Kwiek, whose knowledge in virology and sciences have broadened my perspectives and fostered my critical thinking. I truly appreciate their valuable advice on my candidacy exams and projects overall, as well as their flexibility for coordination of my committee meetings and dissertation defense. I would also wish to extend to my gratitude to Drs. A. Dusty Miller, Chen Liang, Jianrong Li, and Li Wu, whom I have collaborated with during my PhD training in Dr. Liu’s lab, some of which are not included due to space limitation. I would like to thank all members of the Liu lab, both present and past. Dr. Yi-Min Zheng has amazed me for her expertise in both science and cooking. Her words “Those who are good at experiments ought to have a clever hand in cooking” indeed make a lot of sense to me. So many times, have she and Dr. Liu invited the lab members to their house to celebrate holidays and events, which are among the happiest hours for all of us. Dr. Minghua Li was assigned to train my experimental techniques since I joined in the Dr. Liu’s lab. I learned a lot from him, not only on how to conduct the bench work but also the sincere attitude of how to do careful experiments. Dr. Chunhui Miao had helped me to survive a few homeless days when I first arrived at Columbia, vi Missouri - the popular and classic inspirational songs in his car are always unforgettable to me! Many thanks to Drs. Fushun Zhang, Jordan Wilkins, Xuetao Bai and Cong Zeng for their thoughtful discussions on my projects and the harmonious and friendly laboratory atmosphere that we all have built. Thank Dr. Wessel Dirksen, Vaibhav Murthy for their help in editing this thesis. Thanks should go to my friends along the way, Qi Yan from Dr. Yasuko Rikihisa’ lab, Anzhong Li from Dr. Jianrong Li’s lab, as well as all members from Drs. Li Wu, Patrick Green and Sanggu Kim’s lab at the Center for Retrovirus Research. Finally, I am indebted to my parents, my parents-in-law and my wife for their continuous support, encouragement and love. In particular, I desire to thank my little son, Noah Yu, for the laughter that he has brought to us and for the incentives that spur me to strive for the next chapter of my life. vii Vita 2005……………………………………………….. No.1 High School of Taoyuan County, Changde, Hunan Province, China 2009……………………………………………….. B.S., Microbiology and Immunology, China Agricultural University, Beijing, China 2009……………………………………………….. B.Admin., Bio-industry Management, China Agricultural University, Beijing, China 2012……………………………………………….. M.S., Dept. of Virology, Wuhan University, Wuhan, China 2013 to 2016……………………………………… Ph.D. Student, Veterinary Pathobiology, University of Missouri, Columbia, Missouri 2016 to 2018……………………………………. Ph.D. Student, Veterinary Biosciences, The Ohio State University, Columbus, Ohio Publications 1. Yu J, Zheng YM, Liu SL. 2018. Zika Virus Down-regulates AXL and TIM-1 For Optimal Spread. In preparation. 2. Yu J, Liang C, Liu SL. 2018. A CD4-dependent Inhibitory Effect of LY6E on HIV-1 Entry. Journal of Virology, In revision. 3. Yu J, Liu SL. 2018. The Inhibition of HIV-1 Entry Imposed by Interferon Inducible Transmembrane Proteins Is Independent of Co-Receptor Usage. Viruses 10 (8), 413. 4. Lu W, Chen S, Yu J, Behrens R, Wiggins J, Sherer N, Liu SL, Xiong Y, Xiang SH, Wu L. 2018. Three residues in the polar region of HIV-1 gp41 determine viral fusion and infectivity. Cell Reports, under review. 5. Li M*, Waheed A*, Yu J*, Zheng YM, et al. Nef Antagonizes TIM-mediated Inhibition of HIV-1 Release: Role of SERINCs. Proc. Natl. Acad. Sci. U.S.A, in submission. 6. Li A, Yu J, Lu M, Ma Y, Attia Z, Shan C, He J, Liang X, Xue M, Jennings R, Shi PY, Peeples M, Liu SL, Boyaka P, Li J.
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