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PhD Dissertation_WW_11-14-2013_new.pdf (6.59 MB)

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Characterization of Human Lysyl-tRNA Synthetase- and Retroviral Nucleocapsid Protein- Nucleic Acid Interactions

Wang, Wei
http://rave.ohiolink.edu/etdc/view?acc_num=osu1384346307

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Chemistry.
Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that causes acquired immune deficiency syndrome (AIDS). As for other retroviruses, its single-stranded RNA genome is converted into double-stranded DNA in a process called reverse transcription. Although many effective anti-HIV drugs are available, mutations accumulate, which results in drug resistance. Thus, new therapeutic strategies are continuously needed and a more detailed understanding of the viral life cycle will facilitate drug development. The work presented here focuses on two aspects of HIV-1 and other related retroviruses: (1) the packaging of human lysyl-tRNA synthetase (LysRS) into the newly-formed virus particles and, (2) the nucleic acid (NA) interactions and chaperone function of retroviral nucleocapsid proteins (NC). During the assembly step, the HIV-1 structural protein Gag interacts with many cellular and viral factors at the plasma membrane to form new HIV-1 particles. Human LysRS is specifically packaged into HIV-1 and this host factor is believed to be responsible for the selective packaging of tRNALys3, the primer used by HIV-1 in reverse transcription. Previous studies showed that Gag alone is sufficient for LysRS packaging. More specifically, the capsid (CA) C-terminal domain (CTD) of Gag and motif 1 of LysRS are directly involved. Using systematic evolution of ligand by exponential enrichment (SELEX), RNA aptamers that can bind human LysRS have been selected (chapter 2). These RNAs share consensus motifs, which may directly bind LysRS. Their ability to inhibit Gag-LysRS interaction and LysRS packaging will be tested. The possibility of using peptides derived from Gag-LysRS interaction motifs to inhibit their interactions was also studied (chapter 5). Retroviral NC protein is a NA interacting and chaperone protein. It is involved in many critical steps during the retroviral life cycle and even small alterations of this protein greatly reduce viral infectivity. Thus, NC has been proposed to be a promising drug target. For HIV-1, studies have shown that the virus containing a NC precursor (NCp15) is non-infectious, whereas the virus containing another form of precursor (NCp9) is still viable. In chapter 3, the NA interaction and chaperone function of mature HIV-1 NCp7, NCp9 and NCp15 were compared. Although the NA binding, sedimentation, destabilization and annealing activities of the three are similar, NCp15 seems to form distinct NA aggregates. The interaction between the N-terminal domain and CTD of NCp15 appears to be responsible for its distinct NA interacting properties. In chapter 4, the NC from a related retrovirus, feline immunodeficiency virus (FIV), was studied in detail. Finally in chapter 5, a minimal construct responsible for the chaperone activity of HIV-1 NC is defined.
Karin Musier-Forsyth (Advisor)
Dehua Pei (Committee Member)
Zhengrong Wu (Committee Member)
244 p.
Biochemistry; Chemistry

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Citations

  • Wang, W. (2013). Characterization of Human Lysyl-tRNA Synthetase- and Retroviral Nucleocapsid Protein- Nucleic Acid Interactions [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1384346307

    APA Style (7th edition)

  • Wang, Wei. Characterization of Human Lysyl-tRNA Synthetase- and Retroviral Nucleocapsid Protein- Nucleic Acid Interactions. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1384346307.

    MLA Style (8th edition)

  • Wang, Wei. "Characterization of Human Lysyl-tRNA Synthetase- and Retroviral Nucleocapsid Protein- Nucleic Acid Interactions." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1384346307

    Chicago Manual of Style (17th edition)

osu1384346307
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