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Determinants of Hiv-1 Transmission Fitness University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Determinants Of Hiv-1 Transmission Fitness Shilpa Iyer University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Virology Commons Recommended Citation Iyer, Shilpa, "Determinants Of Hiv-1 Transmission Fitness" (2017). Publicly Accessible Penn Dissertations. 2355. https://repository.upenn.edu/edissertations/2355 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2355 For more information, please contact [email protected]. Determinants Of Hiv-1 Transmission Fitness Abstract DETERMINANTS OF HIV-1 TRANSMISSION FITNESS Shilpa S. Iyer Beatrice H. Hahn HIV-1 is predominantly transmitted by mucosal routes and almost 80 percent of new infections are initiated by a single variant. The elucidation of the biological properties of transmitted viruses which distinguish them from non-transmitted variants are critical for the development of therapeutic interventions. To identify such properties, we characterized the biology of 300 limiting dilution-derived virus isolates from the plasma and genital secretions of eight HIV-1 donor and recipient transmission pairs representing the most prevalent subtypes (B and C). Recipient viruses were more infectious per viral particle as determined on a reporter cell line, replicated to higher titers and were released more efficiently from infected primary CD4+ T cells than the corresponding donor isolates. Recipient viruses were more resistant to the inhibitory effects of IFN-α2 and IFN-β evidenced as higher half-maximal inhibitory concentrations and higher replication at the maximal doses of IFN-α2 and IFN-β than corresponding donor isolates. Interestingly, pretreatment of CD4+ T cells with IFN-β, but not IFN-α2 selected donor plasma isolates that exhibited phenotypes similar to transmitted viruses. This suggests that transmitted variants are distinct and that the selective pressure imposed by type I interferons may in part be responsible for the bottleneck associated with mucosal transmission. We next wanted to assess the role of the interferon stimulated gene, tetherin in the antiviral state established by type I IFNs. Thus, we introduced mutations into the vpu gene of various HIV-1 constructs to specifically disrupt their Vpu- mediated tetherin antagonism, and determined the effect on replication and release from infected cells in the presence and absence of IFN-α2. Mutations at key residues in Vpu reduced the viral particle production and release from infected primary CD4+ T cells and this was particularly evident in IFN- α2-treated cells. Interestingly, transmitted HIV-1 variants were released to higher levels from infected cells than chronic control viruses, even in the absence of Vpu. Thus, the counteraction of tetherin resulting in efficient particle release is an important determinant of the interferon resistance of mucosally transmitted HIV-1. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Beatrice H. Hahn Keywords Fitness, HIV-1, Mucosal Transmisison, Type I Interferon Subject Categories Microbiology | Virology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2355 DETERMINANTS OF HIV-1 TRANSMISSION FITNESS Shilpa S. Iyer 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 2017 Supervisor of Dissertation Beatrice H. Hahn, MD Professor of Medicine and Microbiology Graduate Group Chairperson Daniel S. Kessler, Ph. D Associate Professor of Cell and Developmental Biology Dissertation Committee Paul F. Bates, Ph.D., Professor of Microbiology Robert W. Doms, M.D., Ph.D., Pathologist-in-chief, Childrens Hospital of Pennsylvania James A. Hoxie, M.D., Professor of Medicine E. John Wherry, Ph.D., Richard and Barbara Schiffrin President's Distinguished Professor ACKNOWLEDGMENTS I thank my mentor, Dr. Beatrice Hahn. It has been my privilege to be mentored by such an inspiring scientist. She showed faith in me at times when I was lacking in confidence, challenged me when I needed a push and inspired me to constantly give my best. In addition to scientific rigor, she taught me the art of effective communication, a skill that I hope to continue to hone over the years. I thank Dr. Hahn for her unrelenting support and encouragement while I pursued multiple projects and enjoyed the creative process of scientific pursuit. Her ability to cut straight to the crux of the matter, her keen intellect and her passion for excellence inspire me as a woman scientist. I thank Dr. George Shaw for his deeply insightful comments over the past years, and his expert guidance in ‘defining the question’. He taught me to take a step back and consider the big picture, and for his time and guidance, I will always be grateful. I would not have been prepared for the challenge of my graduate career were it not for the dedication and efforts of my undergraduate professors and mentors. They encouraged me to think outside the box and were patient with my many questions. I specially thank Dr. Saroj Ghaskadbi and Dr. Deepti Deobagkar for their role in shaping my scientific career. I have been fortunate to be a part of multiple, productive collaborative projects. Through one such project, I have had the fortune of working with Dr. Persephone Borrow. She has been incredibly generous with her time and very encouraging of my work over the years. Similarly, I was lucky to work closely with Dr. Robert Doms on a project and learn the skill of finding the best approach to answer a question. To these informal mentors, I offer my deepest gratitude. My committee members Dr. Paul Bates, Dr. Robert Doms, Dr. James Hoxie and Dr. John Wherry challenged me to think critically, be creative and provided unparalleled guidance to improve my work. The path to a Ph. D is a long one, and I was lucky to have many friends and colleagues to help make the road easier. I am grateful to fellow Shaw-Hahn lab students – Dr. Rebecca Rudicell, Dr. Rui Kong, Dr. Michael Lopker, Dr. Mark Stoddard and Dr. Edward Kreider for helpful ii discussions and support. I am especially grateful to Dr. Nicholas Parrish for his patience and guidance during my first few years in the lab, and Erica Parrish for her many roles including close friend and constant support system. I would like to thank Dr. Hannah Barbian, Dr. Sesh Sundararaman and Ronnie Russell for their unwavering support and scientific counsel. I am fortunate to have spent my graduate career in a lab with so many generous and skilled scientists: Julie Decker, Juliet Easlick, Jesus Salazar-Gonzales, Maria Salazar, Hui Li, Yingying Li, Jerry Learn, Andrew Smith, Shuyi Wang, Weimin, Elizabeth Loy and Stephanie Trimboli. Among my lab mates, I have learnt the most from Frederic Bibollet-Ruche, who has both encouraged me when times were tough, and pushed me to realize my potential. In him, I gained an undeserved friend and teacher, and I owe him most of my laboratory skills. I am grateful to Katherine J. Bar who served as both a scientific sounding board and personal therapist and ‘tea buddy’. I am also deeply grateful for the tutelage of the late Matthias H. Kraus. I was lucky to work closely with him, and I hope that my graduate work will reflect well on his teaching. I am particularly grateful to Scott Sherill-Mix for his patience and composure while trying to teach me the importance of Bayesian analysis, and to Erik Clarke for much-needed perspective and a sense of optimism. I was fortunate to be able to attend many conferences during my graduate career, and even more fortunate to call Daniel Sauter my friend. From him I learnt the value of endless curiosity and I cherish our many scientific discussions. I especially thank my parents who encouraged my pursuit of the sciences. My mom has patiently supported me these many years and stood by me through everything. Of her limitless love, I am undeserving, yet grateful. I am thankful to my brother, Siddharth, and my extended family for their loving support and strength. This dissertation would not have been possible without the love and help of my husband, Dr. Ranjit Warrier. Thank you for always believing in me, and helping me see the positive side of things. I thank my family of friends who have been my pillars of strength especially Kanupriya Whig, Zahra Parker, Shalini Choudhury, Cory Windsor and Casey Hofstaedtar. Finally, I am grateful to my dad who taught me the importance of integrity and never giving up, I hope my dissertation is an honour to his memory. iii ABSTRACT DETERMINANTS OF HIV-1 TRANSMISSION FITNESS Shilpa S. Iyer Beatrice H. Hahn HIV-1 is predominantly transmitted by mucosal routes and almost 80 percent of new infections are initiated by a single variant. The elucidation of the biological properties of transmitted viruses which distinguish them from non-transmitted variants are critical for the development of therapeutic interventions. To identify such properties, we characterized the biology of 300 limiting dilution-derived virus isolates from the plasma and genital secretions of eight HIV-1 donor and recipient transmission pairs representing the most prevalent subtypes (B and C). Recipient viruses were more infectious per viral particle as determined on a reporter cell line, replicated to higher titers and were released more efficiently from infected primary CD4+ T cells than the corresponding donor isolates. Recipient viruses were more resistant to the inhibitory effects of IFN-α2 and IFN-β evidenced as higher half-maximal inhibitory concentrations and higher replication at the maximal doses of IFN-α2 and IFN-β than corresponding donor isolates. Interestingly, pretreatment of CD4+ T cells with IFN-β, but not IFN-α2 selected donor plasma isolates that exhibited phenotypes similar to transmitted viruses.
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