{"id":{"repo_id":"umn","oai_identifier":"oai:conservancy.umn.edu:11299/194556"},"canonical_url":"https://search.dev.ndltd.org/etd/umn/oai:conservancy.umn.edu:11299/194556","repository":{"repo_id":"umn","name":"University of Minnesota","base_url":"https://conservancy.umn.edu/server/oai/request"},"display":{"title":"Studies On The Determinants Of HIV Mutagenesis And Strategies For Its Enhancement","abstract":"Human immunodeficiency virus type-1 (HIV-1) is one of the fastest evolving entities on earth, due in part to a mutation rate that is at least 10,000-fold higher than that of eukaryotic genomic DNA. The adaptability of HIV-1 prevents clearance of the virus by the immune system, promotes drug resistance, and has impeded development of effective vaccines. The viral mutation rate is a composite result of mutations that are contributed by multiple host and viral enzymes involved in viral replication. However, the precise determinants of viral mutagenesis in HIV-1 and the degree of their contribution to HIV-1 genetic diversity remain incompletely understood. Furthermore, differences in viral mutagenesis among different HIV types (e.g., HIV-1 and human immunodeficiency virus type 2, HIV-2) and subtypes have not been explored to date. Lastly, the elimination of HIV-1 infectivity by increasing the viral mutation rate has not been extensively investigated – in terms of mechanism of action and in preclinical and clinical evaluations. Based upon these general observations, this dissertation research was conducted to test the following hypotheses: 1) HIV-1 and HIV-2 have different mutation rates; 2) decitabine, a HIV-1 mutagen, creates G-to-C transversion mutations in the absence of mutational hotspots; 3) 5-azacytidine causes HIV-1 mutagenesis after reduction to 5-aza-2’-deoxycytidine (i.e. decitabine); 4) the anti-HIV-1 activity of 5-azacytidine is antagonized by inhibitors of ribonucleotide reductase; 5) the anti-HIV-1 activity of ribonucleotide reductase inhibitors are potentiated by 5,6-dihydro-5-aza-2’-deoxycytidine. The studies conducted in this dissertation advance current understanding of the determinants for retroviral mutagenesis, the mechanisms by which small molecules promote mutations in HIV-1, and approaches for using combinations of small molecules to reduce viral infectivity by enhancing the mutagenesis of HIV-1. Supplementary data (figures, tables, and spreadsheets) associated with this thesis are available online.","abstract_html":"Human immunodeficiency virus type-1 (HIV-1) is one of the fastest evolving entities on earth, due in part to a mutation rate that is at least 10,000-fold higher than that of eukaryotic genomic DNA. The adaptability of HIV-1 prevents clearance of the virus by the immune system, promotes drug resistance, and has impeded development of effective vaccines. The viral mutation rate is a composite result of mutations that are contributed by multiple host and viral enzymes involved in viral replication. However, the precise determinants of viral mutagenesis in HIV-1 and the degree of their contribution to HIV-1 genetic diversity remain incompletely understood. Furthermore, differences in viral mutagenesis among different HIV types (e.g., HIV-1 and human immunodeficiency virus type 2, HIV-2) and subtypes have not been explored to date. Lastly, the elimination of HIV-1 infectivity by increasing the viral mutation rate has not been extensively investigated – in terms of mechanism of action and in preclinical and clinical evaluations. Based upon these general observations, this dissertation research was conducted to test the following hypotheses: 1) HIV-1 and HIV-2 have different mutation rates; 2) decitabine, a HIV-1 mutagen, creates G-to-C transversion mutations in the absence of mutational hotspots; 3) 5-azacytidine causes HIV-1 mutagenesis after reduction to 5-aza-2’-deoxycytidine (i.e. decitabine); 4) the anti-HIV-1 activity of 5-azacytidine is antagonized by inhibitors of ribonucleotide reductase; 5) the anti-HIV-1 activity of ribonucleotide reductase inhibitors are potentiated by 5,6-dihydro-5-aza-2’-deoxycytidine. The studies conducted in this dissertation advance current understanding of the determinants for retroviral mutagenesis, the mechanisms by which small molecules promote mutations in HIV-1, and approaches for using combinations of small molecules to reduce viral infectivity by enhancing the mutagenesis of HIV-1. Supplementary data (figures, tables, and spreadsheets) associated with this thesis are available online.","abstract_has_math":false,"creators":["Rawson, Jonathan"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-12","date_published":"2015-12","updated_at":"2026-07-24T05:19:58Z","subjects":["antiviral","HIV","lethal mutagenesis","retrovirus","viral evolution","virus mutation"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/11299/194556","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Rawson, Jonathan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2018-03-14T19:28:24Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2018-03-14T19:28:24Z"]},{"key":"dc:date.issued","label":"Date","values":["2015-12"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["antiviral","HIV","lethal mutagenesis","retrovirus","viral evolution","virus mutation"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/11299/194556"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["University of Minnesota Ph.D. dissertation. December 2015. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Louis Mansky. 1 computer file (PDF); xii, 374 pages + 5 supplementary files"]},{"key":"dc:description.abstract","label":"Abstract","values":["Human immunodeficiency virus type-1 (HIV-1) is one of the fastest evolving entities on earth, due in part to a mutation rate that is at least 10,000-fold higher than that of eukaryotic genomic DNA. The adaptability of HIV-1 prevents clearance of the virus by the immune system, promotes drug resistance, and has impeded development of effective vaccines. The viral mutation rate is a composite result of mutations that are contributed by multiple host and viral enzymes involved in viral replication. However, the precise determinants of viral mutagenesis in HIV-1 and the degree of their contribution to HIV-1 genetic diversity remain incompletely understood. Furthermore, differences in viral mutagenesis among different HIV types (e.g., HIV-1 and human immunodeficiency virus type 2, HIV-2) and subtypes have not been explored to date. Lastly, the elimination of HIV-1 infectivity by increasing the viral mutation rate has not been extensively investigated – in terms of mechanism of action and in preclinical and clinical evaluations. Based upon these general observations, this dissertation research was conducted to test the following hypotheses: 1) HIV-1 and HIV-2 have different mutation rates; 2) decitabine, a HIV-1 mutagen, creates G-to-C transversion mutations in the absence of mutational hotspots; 3) 5-azacytidine causes HIV-1 mutagenesis after reduction to 5-aza-2’-deoxycytidine (i.e. decitabine); 4) the anti-HIV-1 activity of 5-azacytidine is antagonized by inhibitors of ribonucleotide reductase; 5) the anti-HIV-1 activity of ribonucleotide reductase inhibitors are potentiated by 5,6-dihydro-5-aza-2’-deoxycytidine. The studies conducted in this dissertation advance current understanding of the determinants for retroviral mutagenesis, the mechanisms by which small molecules promote mutations in HIV-1, and approaches for using combinations of small molecules to reduce viral infectivity by enhancing the mutagenesis of HIV-1. Supplementary data (figures, tables, and spreadsheets) associated with this thesis are available online."]},{"key":"dc:title","label":"Title","values":["Studies On The Determinants Of HIV Mutagenesis And Strategies For Its Enhancement"]}]}],"canonical_facts":{"dc:creator":["Rawson, Jonathan"],"dc:date.accessioned":["2018-03-14T19:28:24Z"],"dc:date.available":["2018-03-14T19:28:24Z"],"dc:date.issued":["2015-12"],"dc:description":["University of Minnesota Ph.D. dissertation. December 2015. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Louis Mansky. 1 computer file (PDF); xii, 374 pages + 5 supplementary files"],"dc:description.abstract":["Human immunodeficiency virus type-1 (HIV-1) is one of the fastest evolving entities on earth, due in part to a mutation rate that is at least 10,000-fold higher than that of eukaryotic genomic DNA. The adaptability of HIV-1 prevents clearance of the virus by the immune system, promotes drug resistance, and has impeded development of effective vaccines. The viral mutation rate is a composite result of mutations that are contributed by multiple host and viral enzymes involved in viral replication. However, the precise determinants of viral mutagenesis in HIV-1 and the degree of their contribution to HIV-1 genetic diversity remain incompletely understood. Furthermore, differences in viral mutagenesis among different HIV types (e.g., HIV-1 and human immunodeficiency virus type 2, HIV-2) and subtypes have not been explored to date. Lastly, the elimination of HIV-1 infectivity by increasing the viral mutation rate has not been extensively investigated – in terms of mechanism of action and in preclinical and clinical evaluations. Based upon these general observations, this dissertation research was conducted to test the following hypotheses: 1) HIV-1 and HIV-2 have different mutation rates; 2) decitabine, a HIV-1 mutagen, creates G-to-C transversion mutations in the absence of mutational hotspots; 3) 5-azacytidine causes HIV-1 mutagenesis after reduction to 5-aza-2’-deoxycytidine (i.e. decitabine); 4) the anti-HIV-1 activity of 5-azacytidine is antagonized by inhibitors of ribonucleotide reductase; 5) the anti-HIV-1 activity of ribonucleotide reductase inhibitors are potentiated by 5,6-dihydro-5-aza-2’-deoxycytidine. The studies conducted in this dissertation advance current understanding of the determinants for retroviral mutagenesis, the mechanisms by which small molecules promote mutations in HIV-1, and approaches for using combinations of small molecules to reduce viral infectivity by enhancing the mutagenesis of HIV-1. Supplementary data (figures, tables, and spreadsheets) associated with this thesis are available online."],"dc:identifier.uri":["http://hdl.handle.net/11299/194556"],"dc:language.iso":["en"],"dc:subject":["antiviral","HIV","lethal mutagenesis","retrovirus","viral evolution","virus mutation"],"dc:title":["Studies On The Determinants Of HIV Mutagenesis And Strategies For Its Enhancement"],"dc:type":["Thesis or Dissertation"]},"updated_at":"2026-07-24T05:19:58Z"}