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HIV-1 Elimination in Humanized Mice

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HIV-1 Elimination in Humanized Mice University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Fall 12-20-2019 HIV-1 Elimination in Humanized Mice Hang Su University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Virus Diseases Commons Recommended Citation Su, Hang, "HIV-1 Elimination in Humanized Mice" (2019). Theses & Dissertations. 407. https://digitalcommons.unmc.edu/etd/407 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. HIV-1 Elimination in Humanized Mice by Hang Su A Dissertation Presented to the Faculty of the Graduate School in the University of Nebraska Medical Center in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Department of Pharmacology and Experimental Neuroscience Under the Supervision of Professor Howard E. Gendelman University of Nebraska Medical Center Omaha, Nebraska October 2019 Supervisory Committee: Prasanta K. Dash, Ph.D. Tatiana K. Bronich, Ph.D. Larisa Y. Poluektova, M.D., Ph.D. Angie Rizzino, Ph.D. Samuel M. Cohen, M.D., Ph.D. ii Acknowledgements First of all, I would like to thank my mentor Dr. Howard E. Gendelman, for all these years’ unconditional guidance and support. His foresight in science keeps us at the frontier of the field and shows us the way of thinking. His hard working motivates us to expand our limitations and complete missions that once seemed impossible. He always immerses his wisdom in his humor and teaches us to be optimistic about life. His passion in science encourages us to pursue and succeed in what we do. I would like to thank my committee members Drs. Prasanta K. Dash, Tatiana K. Bronich, Larisa Y. Poluektova, Angie Rizzino, and Samuel M. Cohen for their consistent guidance, suggestions, and support over the years. I want to specially thank Dr. Dash for his day-to-day supervision, training, and support. I appreciate his support as both a mentor and close friend. I would like to thank Dr. Poluektova and Dr. Santhi Gorantla for their support on both science and daily life through the years. I would like to thank all the former and current Gendelman’s lab members for their all-time support and friendship, which includes but not limited by Drs. Mariluz Arainga, Divua Prakash, Midhun Ben Thomas, Bhavesh Kevadiya, Saumi Mathews, JoEllyn McMillan, Benson Edagwa, R. Lee Mosley, Charles Schutt, Kate Olson, Weizhe Li, Tian Zhou, Brady Sillman, Zhiyi Lin, James R. Hilaire, Aditya N. Bade, Ibrahim Ibrahim, Mary Banoub and Denise Cobb, Diana Palandri, Mahmudui Hasan, Jonathan Herskovitz, Tanmay Kulkarni, Insiya Mukadam, Brendan Ottemann, Dhruvkumar Soni, Sruthi Sravanam, Yan Cheng, Lili Guo, Li Wu, Weimin Wang, and Edward Makarov. iii I would like to thank the Chinese Scholarship Council and UNMC fellowship for the financial support during my PhD training. I would like to thank the committee and friends in UNMC MD/PhD program for your support and friendship. I would like to thank all administrative staff at UNMC Graduate Studies and Department of Pharmacology and Experimental Neuroscience for the many years of support. I would like to thank the staff in UNMC core research and animal facilities for their support. I would like to thank my parents, Guobin Su and Yanbin Liu, for their understanding, love, support, and sacrifice. They always supported me on whatever I choose to do and put me first above all else. I wouldn’t be who I am without them. I also wouldn’t survive without my friends on and off campus. Their lifelong friendship is invaluable treasure. One person is too small. I am only standing here because all of you around me. Hang Su October 2019 iv Abstract HIV-1 Elimination in Humanized Mice Hang Su, Ph.D. University of Nebraska Medical Center, 2019 Supervisor: Howard E. Gendelman, M.D. Human immunodeficiency virus type one (HIV-1) exclusively infects humans and chimpanzees. Therefore, animal models are required for all investigations of viral pathogenesis, therapy and cure. Immunodeficient mice transplanted with human hematopoietic stem cells, termed humanized mice, support the development of multiple human cell lineages throughout the cell’s life span. To this end, we used humanized mice to evaluate the dynamic changes of host immunologic and viral profiles during both acute and chronic HIV-1 infection. We identified the temporal and spatial distribution of HIV-1 cell and tissue compartment infections and outlined correlations made between viral progression and host immunity by comparing two different humanized mouse models. Based on the discovery of early viral set-points, we developed a paradigm for a potential ‘HIV-1 cure’ by sequential administration of long-acting slow-effective release antiretroviral therapy (LASER ART) and CRISPR-Cas9 treatments. HIV-1 elimination was achieved in a third of dual-treated humanized mice after exhaustive works to detect HIV-1 and its gene products in peripheral blood, brain, lung, liver, spleen, kidney, gut, and bone marrow (BM). This was done by sensitive nested and digital-droplet PCR and RNAscope tests. Immune function was preserved in animals where HIV-1 was eliminated. In vivo viral outgrowth assay (VOA) was employed to confirm HIV-1 elimination by adoptive transfer of donor splenocytes and BM cells into naïve humanized mice. While v virus was successfully recovered from HIV-1 control, LASER ART or CRISPR-Cas9 alone treated animals virus could not be recovered in recipients transplanted from a third of the dual-treated “cured” animals. We further characterized the impact of humanized mice-based VOA in viral isolation assay by expanding the sample sizes. We observed that replication-competent HIV-1 persisted in multiple tissues even when plasma viral load was undetectable and virus can be readily recovered from naïve humanized mice. We demonstrate that in vivo VOA using humanized mice is a sensitive assay system to interrogate replication competent HIV-1 and can be employed to determine viral eradication from donor samples. To this end, we used the humanized mouse model to study HIV-1 tissue compartmentalization, interrogate HIV-1 eradication employing innovative technologies, and assess HIV-1 elimination using humanized mice-based VOA, which will facilitate future translational studies. vi Table of Contents Acknowledgements ................................................................................................. ii Abstract .................................................................................................................. iv Table of Contents ................................................................................................... vi List of Figures ......................................................................................................... x List of Tables ........................................................................................................ xii List of Abbreviation ............................................................................................. xiii Chapter 1 Introduction ............................................................................................ 1 1.1 HIV-1 RESERVOIRS ........................................................................................ 2 1.2 ANIMAL MODELS FOR STUDIES OF HIV-1 PATHOGENESIS .............................. 5 1.3 STRATEGIES FOR HIV-1 CURE ........................................................................ 8 Chapter 2 Immune Activations and Viral Tissue Compartmentalization During Progressive HIV-1 Infection of Humanized Mice ................................................ 19 2.1 ABSTRACT .................................................................................................... 20 2.2 INTRODUCTION............................................................................................. 21 2.3 MATERIALS AND METHODS ......................................................................... 22 2.3.1 Ethics Statement ................................................................................... 23 2.3.2 Generation and HIV-1 infection of humanized mice ........................... 23 2.3.3 Flow cytometry..................................................................................... 24 2.3.4 Viral load analyses .............................................................................. 24 2.3.5 Nucleic acid extraction and quantification .......................................... 25 vii 2.3.6 RNAscope ............................................................................................. 25 2.3.7 Immunohistochemistry ......................................................................... 26 2.3.8 Human mRNA analysis of immune responses ...................................... 26 2.3.9 Statistical analyses ............................................................................... 26 2.4 RESULTS ...................................................................................................... 27 2.4.1 Immune profiles in HIV-1 infected humanized mice ............................ 27 2.4.2 Plasma viral loads in HIV-1 infected humanized mice ........................ 31 2.4.3 Tissue compartments in HIV-1 infected humanized mice .................... 32 2.4.4 Confirmatory tests of viral gene expression in infected humanized mice ..................................................................................................................................
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