The limitations of HIV-1 therapeutics, which include viral drug resistance and off-target effects, provide the impetus for the identification of novel drug targets and the development of new anti-HIV-1 drugs. Previous in vitro data found that the combination of two clinically approved drugs, decitabine and gemcitabine, reduced HIV-1 infectivity by 73% at concentrations that had minimal antiviral activity when used individually. Decreased infectivity coincided with a significant increase in mutant frequency and a shift in the HIV-1 mutant spectra by combining a nucleoside analog that forms non-canonical base pairs with certain ribonucleotide reductase inhibitors. Increased mutational load is implicated as the primary antiviral mechanism for inhibiting the generation of infectious progeny virus from provirus, and support a model in which increased mutation frequency decreases infectivity through lethal mutagenesis. In this application, we propose to test the hypothesis that error-prone viral replication may induce "error catastrophe" or extinction in vivo due to an accumulation of deleterious mutations. Strategies designed to drive viruses to error catastrophe have been applied to HIV-1 and a number of RNA viruses however for the most part they have not been evaluated in vivo for their ability to effectively control HIV replication. Here, we propose to use a novel humanized mouse model to investigate 1) the ability of decitabine and gemcitabine to control viral replication in vivo, and 2) the ability of the decitabine/gemcitabine drug combination to control HIV replication in vivo by elevating the viral mutational load.
HIV-1 drug resistance and side effects can limit the long-term effectiveness of antiretroviral activity, requiring the continual need for the identification of novel drug targets and the development of new anti-HIV-1 drugs.
|Dapp, Michael J; Bonnac, Laurent; Patterson, Steven E et al. (2014) Discovery of novel ribonucleoside analogs with activity against human immunodeficiency virus type 1. J Virol 88:354-63|
|Rawson, Jonathan M; Heineman, Richard H; Beach, Lauren B et al. (2013) 5,6-Dihydro-5-aza-2'-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors. Bioorg Med Chem 21:7222-8|
|Krisko, John F; Martinez-Torres, Francisco; Foster, John L et al. (2013) HIV restriction by APOBEC3 in humanized mice. PLoS Pathog 9:e1003242|