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Role of Human T-Lymphotropic Virus Type 1 P30(Ii) And

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Role of Human T-Lymphotropic Virus Type 1 P30(Ii) And ROLE OF HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 P30(II) AND SURFACE ENVELOPE AS DETERMINANTS OF IN VIVO PATHOGENESIS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Lee Silverman, DVM, DACVP * * * * * The Ohio State University 2005 Dissertation Committee: Approved by Dr. Michael Lairmore, Advisor Dr. Kathleen Boris-Lawrie Advisor Dr. Natarajan Muthusamy Veterinary Biosciences Graduate Dr. Thomas Rosol Program ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is the first identified human retrovirus. It is the causative agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paresis, and it has been implicated in a variety of other immune-mediated disorders such as dermatitis, polymyositis, and uveitis. HTLV-1 exhibits high genetic stability in vivo. In addition to the canonical retroviral gag, pol, and env genes, HTLV-1 contains four open reading frames (ORF) in its pX region. ORF II encodes two proteins, p30II and p13II, both of which are incompletely characterized. p30II localizes to the nucleus/nucleolus and has distant homology to the transcription factors, Oct-1, Pit-1, and POU-M1. p30II modulates cellular and viral gene expression at the transcriptional and post-transcriptional level. Herein, we determine the in vivo significance of p30II by inoculating rabbits with cell lines expressing either a wild-type clone of HTLV-1 (ACH.1) or a clone containing a mutation in ORF II, which eliminated wild-type p30II expression (ACH.30.1). ACH.1-inoculated rabbits maintained higher HTLV-1- specific antibody titers than ACH.30.1-inoculated rabbits, and all ACH.1- inoculated rabbits were seropositive for HTLV-1, whereas only two of six ACH.30.1-inoculated rabbits were seropositive. Provirus could be consistently PCR amplified from peripheral blood mononuclear cell (PBMC) DNA in all ii ACH.1-inoculated rabbits but in only three of six ACH.30.1-inoculated rabbits. Quantitative competitive PCR indicated higher PBMC proviral loads in ACH.1- inoculated rabbits. Interestingly, sequencing of ORF II from PBMCs of provirus positive ACH.30.1-inoculated rabbits revealed a reversion to wild-type sequence with evidence of early coexistence of mutant and wild-type sequence. Our data provide evidence that HTLV-1 must maintain key accessory genes to survive in vivo and that in vivo pressures select for maintenance of wild-type ORF II gene products during the early course of infection. Recent gene array analysis has indicated a role for p30II in modulating cellular expression of a number of apoptosis regulatory genes. Herein, we seek to determine if this translates into a functional role for p30II in modulating cellular apoptosis. ACH.1 or ACH.30.1 lymphocyte cell lines, 293T cells transiently expressing p30II, and Jurkat T cells expressing p30II were induced into apoptosis with camptothecin (targeting cells in the S phase of the cell cycle), etoposide (intrinsic apoptosis pathway), or TRAIL (extrinsic apoptosis pathway). Compared to ACH.1 cells, ACH.30.1 cells showed increased apoptosis induction following treatment with camptothecin, but no difference in apoptosis induction following treatment with etoposide or TRAIL. Transient p30II-expressing 293T cells and lentivirus p30II vector transduced Jurkat T cells showed no differential susceptibility to apoptosis inducing agents compared to empty vector transfected/infected controls. However, expression of p30II in Jurkat T cells reduced cell proliferation by delaying onset of division. We conclude that although HTLV-1 p30II does not modulate susceptibility to iii apoptosis in transformed epithelial cells or T lymphocytes, it does reduce cell proliferation and thereby promotes lymphocyte survival. HTLV-1 Env protein (surface unit, SU, and transmembrane TM) is unique among retroviral Env proteins in that it maintains high amino acid sequence conservation. Previous in vitro assays indicate that HTLV-1 Env Ser75Ile, Asn95Asp, and Asn195Asp SU mutants maintain the ability to replicate in and immortalize lymphocytes. Herein, we examine the effects of these critical Env mutants in rabbits inoculated with HTLV-1 immortalized ACH.75, ACH.95, or ACH.195 cell lines (expressing full length molecular clones with the SU mutations) or ACH.1 cell line (expressing wild-type SU). All rabbits became infected, and the fidelity of the mutations was maintained for the 8 week duration of the study. The ACH.75- and ACH.95 –inoculated rabbits had a decreased overall antibody response to Gag and Env antigens. The ACH.195- inoculated rabbits had a selective decreased antibody response to the Env SU protein. One of four ACH.195 rabbits had detectable proviral loads in PBMCs in the absence of a detectable antibody response, and another of the ACH.195 rabbits mounted an antibody response against both HTLV-1 Gag and Env antigens and HTLV-2 SU protein. ACH.75 rabbits on average had higher PBMC proviral loads compared to ACH.1 and ACH.95 rabbits. PBMC proviral loads, however, did not correlate with antibody responses to SU. Mutations in critical determinants of HTLV-1 SU, while altering proviral loads and antibody responses against Env, did not prevent virus replication in vivo. iv Dedicated to: Sadie and Meyer Greenblatt Mary and Ralph Silverman Wilbur Silvermintz v ACKNOWLEDGMENTS It would not have been possible to complete this work without the support of numerous people on both an academic and personal level. I apologize in advance for forgetting to mention anyone. I acknowledge the following people: Past and current members of the Lairmore laboratory, who were always available for support and advice. Special thanks to Andrew Phipps and Andy Montgomery, with whom I learned how much more productive teamwork can be than working alone. Kate Hayes, Tim Vojt, Soledad Fernandez, and Rick Meister, whose technical support was invaluable in completing these projects. Michael Lairmore, who was the primary advisor on these projects, for continual advice and support and for allowing me to be independent. Special thanks to Michael Lairmore, Kathleen Boris-Lawrie, Natarajan Muthusamy, and Thomas Rosol for serving on my Ph.D. committee. I appreciate their time and interest in my education. K. Nasir Khan, whose intelligence, integrity, and kindness inspired me to embark upon this journey and who has continued to be a source of professional support. vi Laura Rush, Rani Sellers, and Sarah Tannehill-Gregg, whose friendship at various stages in my training was invaluable in getting me through the day. Steven E. Weisbrode, who significantly contributed to my understanding of the word “mentor” and whose integrity never once failed me. Tetsuya and Chizuko Takei, with whom I always have a home and a family. Loretta Silvermintz and family, Max and Betty Bridge and family, and Albert and Sally Greenblatt and family, who have provided an example of what family should be for generations to come, and who are the foundation of the structure on which everything of meaning in my life stands. Arthur and Sheryn Silverman and family, who have been the rock of my thirty-three years of existence, and without whom, completion of this work simply would not have been possible. vii VITA April 30, 1971…………………………Born – St. Louis, Missouri 1993……………………………………B.A. Mathematics and Japanese Washington University, St. Louis, MO 2000……………………………………D.V.M. University of Missouri, Columbia, MO 2000 - present……………………….Graduate Research Associate The Ohio State University, Columbus, OH PUBLICATIONS 1. Silverman, Lee R., Andrew J. Phipps, Andy Montgomery, Lee Ratner and Michael D. Lairmore. (2004). Human T-Lymphotropic Virus Type 1 Open Reading Frame II Encoded p30II is Required for In Vivo Replication: Evidence of In Vivo Reversion. Journal of Virology, 78 (8), 3837-3845. 2. Seller, Rani S., Lee R. Silverman and K. Nasir Khan. (2004). Cyclooxygenase-2 Expression in the Cornea of Dogs with Keratitis. Veterinary Pathology 41 (2), 116-121. viii 3. Marshall, J.L., Kristine M. Stanfield, Lee R. Silverman and K. Nasir Khan. 2004. Enhanced Expression of Cyclooxygenase-2 in Glaucomatous Eyes. Veterinary Ophthalmology 7 (1), 59-62. 4. Ye, Jianxin, Lee R. Silverman, Michael D. Lairmore and Patrick L. Green. 2003. HTLV-1 Rex is Required for Viral Spread and Persistence In Vivo but is Dispensable for Cellular Immortalization In Vitro. Blood 102 (12), 3963-3969. 5. Khan, K. Nasir, Lee R. Silverman, A. Logan and Richard K. Harris. (1999). Paratrichial Sweat Gland Adenocarcinoma in a Marmoset. Journal of Veterinary Diagnostic Investigation 11 (5), 478-480. 6. Khan, K. Nasir, Lee R. Silverman and David A. Baron. (1999). Cyclooxygenase-2 (COX-2) Expression in the Developing Canine Kidney. Veterinary Pathology 35 (5), 486. 7. Silverman, Lee R. and K. Nasir Khan. (1998). Nonsteroidal Anti- Inflammatory Drug-Induced Renal Papillary Necrosis in a Dog. Toxicologic Pathology 27 (2), 244-245. FIELDS OF STUDY Major Field: Veterinary Biosciences ix TABLE OF CONTENTS Page Abstract .................................................................................................................ii Dedication .............................................................................................................v Acknowledgments ................................................................................................vi Vita ..................................................................................................................... viii List of Tables
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