BIOMEDICAL SCIENCES GRADUATE PROGRAM AUTUMN 2014

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1 THE OHIO STATE UNIVERSITY BIOMEDICAL SCIENCES GRADUATE PROGRAM AUTUMN 2014 Nathan James Dissinger PhD Candidate Role of HTLV-1 HBZ and HTLV-2 APH-2 in Disease Outcome November 5 th, Veterinary Medicine Academic Building 9:00 am

2 VITA March 21 st, Born Bethlehem, PA May, BS, Microbiology Pennsylvania State University July2009-Present Graduate Research Associate The Ohio State University COMMITTEE MEMBERS Patrick L. Green, Ph.D., Advisor Jesse Kwiek, Ph.D. W. James Waldman, Ph.D. Mamuka Kvaratskhelia, Ph.D.

3 ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus found to cause disease, including neurological and inflammatory disorders as well as the aggressive T-cell malignancy adult T-cell leukemia/lymphoma (ATL). There is currently no cure for ATL and the median survival length upon onset is one year, even with treatment. Originally the Tax protein of HTLV-1 was considered to be the most important for HTLV-1 associated malignancy, however expression of Tax is lost in about 70% of ATL cases. A gene encoded by the antisense strand of the provirus, HTLV-1 bzip factor (HBZ), was discovered in 2002 and has been shown to be expressed in every case of ATL. HBZ represses Tax transactivation of the sense strand of the HTLV-1 provirus as well as modulates several cellular pathways, including growth and survival pathways. Our lab and others have shown that HBZ is required for efficient viral infection and persistence using a rabbit animal model. Our lab and others have also shown HBZ to be important for the proliferation of HTLV-1 transformed cells. Though classically Tax is considered the oncoprotein of HTLV-1, there is growing evidence that HBZ is one as well. A second retrovirus, HTLV-2, is highly related to HTLV-1 but appears to be much less pathogenic in vivo. HTLV-2 encodes a Tax protein that shares several functions of its HTLV-1 counterpart. HTLV-2 also encodes an HBZ counterpart, APH-2. APH-2 represses Tax transactivation, however we found that, unlike HBZ, APH-2 is dispensable for infection and persistence in vivo. We hypothesize that comparative studies between HBZ and APH-2 will provide insight into HBZ s role in HTLV-1 disease development. In this work, we examined how APH-2 affects pathways known to be modulated by HBZ and are hypothesized to be important for HTLV-1 pathogenesis. We found that APH-2 inhibited transforming growth factor β (TGF-β) signaling while HBZ enhanced it. We also report that HBZ and APH-2 repressed

4 p65- and IRF-1-mediated transcription when HBZ and APH-2 protein expression is equal. However, comparison of the half-lives of APH-2 and HBZ protein as well as their mrna transcript levels in infected cells indicated a more limited functional role for APH-2 during infection. Our findings reveal the importance of HBZ s modulation of these pathways and their potential implications in HTLV-1 pathobiology.

5 RECENT ABSTRACTS AND PRESENTATION Dissinger N Role of HTLV Antisense Strand Encoded Proteins in Viral Pathogenesis. Center of Retrovirus Research- The Ohio State University. Oral Presentation. Dissinger N, Green PL. Differential Induction of Interferon by HTLV-1 and HTLV-2 Leads to Distinct Pathobiologies. The Ohio State University Medical Center Research Day Poster. Dissinger N, Green PL. Related HTLV-1 and HTLV-2 Antisense Proteins (HBZ, APH-2) Have Distinct Effects on Cellular Signaling Pathways. American Society of Virology Conference- Pennsylvania State University Poster. Dissinger N, Green PL Post Translational Modifications of HBZ and Their Role in Protein Function. Veterinary Bioscience Seminar. The Ohio State University.

6 RECENT PUBLICATIONS Yin H, Kannian P, Dissinger N, Haines R, Niewiesk S, et al. (2012) Human T-Cell Leukemia Virus Type 2 Antisense Viral Protein 2 Is Dispensable for In Vitro Immortalization but Functions To Repress Early Virus Replication In Vivo. Journal of Virology 86: doi: /jvi Barrios CS, Dissinger N, Green PL, Beilke MA (2014) Biology, clinical features, and immunology of human T-cell lymphotropic virus type 2. Current Topics in Virology 11: Dissinger N, Shkriabai N, Hess S, Al-Saleem J, Kvaratskhelia M, Green PL. Identification and Characterization of HTLV-1 HBZ Post-Translational Modifications. Revisions in resubmission to PLoS One (10/10/14) Dissinger NJ, Panfil AR, Landes K, Green PL. Functional Comparison of the HTLV-1 and HTLV-2 Antisense Transcribed Proteins, HBZ and APH-2. In preparation for Journal of Virology.

7 AWARDS AND HONORS American Society of Virology Travel Award C. Glenn Barber Award FUTURE PLANS Nathan plans on continuing to work in Dr. Green s lab while searching for a postdoctoral position in the field of viral pathogenesis. He hopes to continue his career in scientific research and maintain a presence in the laboratory setting.

8 Biomedical Sciences Graduate Program 1170 Graves Hall 333 W. 10 th Avenue Columbus, Ohio 43210