Antiretroviral 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.
University of Minnesota Ph.D. dissertation.December 2013. Major: Comparative and Molecular Biosciences. Advisor: Louis Mansky. 1 computer file (PDF); xi, 107 pages.
Studies of feline leukemia virus drug susceptibility and antiviral mechanism of action.
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