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Studies of HIV-1 mutagenesis during drug therapy and the molecular determinants of HIV-1 variation

Chen, Renxiang
http://rave.ohiolink.edu/etdc/view?acc_num=osu1092663963

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Human immunodeficiency virus type 1 is a member of the lentivirus genus of the Retroviridae. HIV-1 exists as a mixture of non-identical but closely related virions, known as “quasispecies”. Therefore, HIV-1 populations demonstrate high levels of genetic variation, which arise through mutation, recombination and selection. This dissertation extends studies of HIV-1 genetic variation in two areas: 1) the influence of antiretroviral drugs and drug-resistant reverse transcriptase (RT) variants on HIV-1 mutant frequencies, and 2) the role of the HIV-1 accessory protein Vpr and cellular DNA repair enzyme uracil-DNA glycosylase (UNG) interaction in HIV-1 mutagenesis. In the first study, the influences of antiretroviral drugs and drug-resistant RT variants on HIV-1 mutant frequencies were tested. Using a new high-throughput assay system, I tested the following hypotheses: 1) All nucleoside RT inhibitors (NRTI’s) currently used in drug therapy increase virus mutant frequencies; 2) Non-nucleoside RT inhibitors (NNRTI’s) can increase virus mutant frequencies; 3) NNRTI-NNRTI drug combination can further increase virus mutant frequencies compared to individual drugs; 4) NRTI-NNRTI drug combination can increase virus mutant frequencies higher than that observed in the presence of individual drugs; 5) High-level, drug-resistant RTs can influence virus mutant frequencies. To better understand the mechanism(s) responsible for the influence of antiretroviral drugs on virus mutant frequencies, I tested the hypothesis that intracellular deoxynucleotide triphosphate (dNTP) levels are altered by antiretroviral drugs. Antiretroviral drugs were observed to alter intracellular dNTP concentrations, suggesting an association to increases in virus mutant frequencies. The second study analyzed Vpr-mediated UNG2 incorporation into virus particles. I tested the hypothesis that UNG2 incorporated into virus particles is catalytically active and may subsequently influence the reverse transcription process and viral replication. Several Vpr-UNG interaction-deficient mutants and Vpr-UNG fusion constructs were tested. I found that UNG activity could be recovered from virus particles only when the Vpr-UNG interaction was maintained. Moreover, the Vpr-UNG fusion proteins were efficiently incorporated into particles, indicating that these fusion proteins can be used to further study the role of UNG in HIV-1 replication.
Louis Mansky (Advisor)
Biology, Molecular
HIV-1; Variation; Drug-resistance; RT mutant

Recommended Citations

Citations

  • Chen, R. (2004). Studies of HIV-1 mutagenesis during drug therapy and the molecular determinants of HIV-1 variation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1092663963

    APA Style (7th edition)

  • Chen, Renxiang. Studies of HIV-1 mutagenesis during drug therapy and the molecular determinants of HIV-1 variation. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1092663963.

    MLA Style (8th edition)

  • Chen, Renxiang. "Studies of HIV-1 mutagenesis during drug therapy and the molecular determinants of HIV-1 variation." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1092663963

    Chicago Manual of Style (17th edition)

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© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.