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Molecular analysis of human t-cell leukemia virus regulatory and accessory proteins

Younis, Ihab H
http://rave.ohiolink.edu/etdc/view?acc_num=osu1123168747

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are closely related pathogenic human retroviruses. Although, they both transform human primary T cells in vitro, in humans, HTLV-1 is the causative agent for ATLL and HAM/TSP, whereas HTLV-2 disease association is less clear. In this dissertation, we report molecular studies regarding the regulation of HTLV replication and its impact on viral persistence in vivo. In Chapter 2, we generate a novel HTLV-1 clone (H1IT) in which the two regulatory proteins, Tax and Rex, have been separated in an attempt to provide a better reagent to study mutants of these proteins in the context of the provirus and analyze their contribution to HTLV-mediated transformation. In vitro data indicates that H1IT is replication competent and is capable of cellular transformation of primary human T-cells. However, H1IT was unable to persist in vivo, emphasizing the importance of temporal and quantitative regulation of Tax RNA to viral replication. In Chapter 3, we report that both HTLV-1 and HTLV-2 have evolved accessory genes whose products are able to restrict viral replication at a post-transcriptional level. The HTLV-1 p30 and the related HTLV-2 p28 proteins inhibit both Tax and Rex by binding to and retaining tax/rex mRNA in the nucleus, thereby inhibiting virion production. In Chapter 4, we show that p28 is recruited to the viral promoter in a Tax-dependent manner. After recruitment to the promoter, p28 or p30 travels with the transcription elongation machinery until its target mRNA is synthesized. Since the above data is consistent with a critical role of these accessory proteins in viral persistence in vivo, in Chapter 5, we used an animal model of HTLV infection to study the specific contribution of p28 on HTLV-2 survival. In this study, all wtHTLV-2 infected rabbits showed persistent infection, whereas those infected with HTLV-2Deltap28 were able to eliminate the virus as early as 2 weeks, indicating that p28 is critical for early viral infectivity, spread and/or persistence in rabbits. Collectively, data presented within this dissertation support the conclusion that the regulation of HTLV gene expression a complicated but a tightly controlled process.
Patrick Green (Advisor)
208 p.
Biology, Molecular
Human T-cell Leukemia Virus; Accessory proteins; Regulatory proteins; posttranscriptional regulation

Recommended Citations

Citations

  • Younis, I. H. (2005). Molecular analysis of human t-cell leukemia virus regulatory and accessory proteins [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1123168747

    APA Style (7th edition)

  • Younis, Ihab. Molecular analysis of human t-cell leukemia virus regulatory and accessory proteins. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1123168747.

    MLA Style (8th edition)

  • Younis, Ihab. "Molecular analysis of human t-cell leukemia virus regulatory and accessory proteins." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1123168747

    Chicago Manual of Style (17th edition)

osu1123168747
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.