Browsing by Subject "antiviral"
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Item Studies of feline leukemia virus drug susceptibility and antiviral mechanism of action(2013-12) Greggs, WillieAntiretroviral drugs have saved and extended the lives of millions of individuals infected with human immunodeficiency virus type 1 (HIV-1). The major classes of anti-HIV-1 drugs include reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and entry/fusion inhibitors. While antiretroviral drug regimens are commonly used to treat other types of retroviral infections, there are instances where there is a perceived need for re-evaluation of the benefits of new antiretroviral therapy. One case in point is that of feline leukemia virus (FeLV), an infection of domesticated felines. While vaccines exist to prevent FeLV infection and spread, they have not eliminated FeLV infection. For FeLV-infected felines and their human companions, antiretroviral therapy would be desirable and of practical importance if good options were available. The goal of this dissertation was to 1) determine the susceptibility of FeLV to drugs that could be amendable to clinical translation, and 2) explore the anti-FeLV mechanism of action of these drugs. FeLV was found to be susceptible to two anticancer drugs (i.e., decitabine and gemcitabine) as well as two anti-HIV-1 drugs (raltegravir and tenofovir). FeLV, but not HIV-1, was also found to be susceptible to cyclopentenyl cytosine. Mechanism of action studies suggested that decitabine and gemcitabine did not enhance FeLV mutagenesis, which is contrary to previous observations of enhanced HIV-1 mutagenesis observed with these drugs. Cyclopentenyl cytosine did not enhance viral mutagenesis, was observed to reduce dCTP levels in the Crandell-Rees feline kidney cell line, and FeLV susceptibility to cyclopentenyl cytosine was enhanced by a mutation in a conserved region of reverse transcriptase. These studies 1) support the further exploration of the clinical translation of decitabine, gemcitabine and cyclopentenyl cytosine for the treatment of FeLV infection, and 2) suggest differences in the antiviral mechanisms of action of decitabine, gemcitabine and cyclopentenyl cytosine between FeLV and HIV-1.Item Studies On The Determinants Of HIV Mutagenesis And Strategies For Its Enhancement(2015-12) Rawson, JonathanHuman 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.