Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461
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Mullins-2011-Mutation of HIV-1 Ge.pdf
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Author(s)
Mullins, James I.
Heath, Laura
Hughes, James P.
Kicha, Jessica
Styrchak, Sheila
Wong, Kim G.
Rao, Ushnal
Hansen, Alexis
Harris, Kevin S.
Laurent, Jean-Pierre
Date Issued
January 2011
Journal
PLoS ONE
Publisher
Public Library of Science
Citation
Mullins, James I. et al. “Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461.” Ed. Reuben S. Harris. PLoS ONE 6.1 (2011) : e15135.
Version
Final published version
Abstract
The deoxycytidine analog KP1212, and its prodrug KP1461, are prototypes of a new class of antiretroviral drugs designed to increase viral mutation rates, with the goal of eventually causing the collapse of the viral population. Here we present an extensive analysis of viral sequences from HIV-1 infected volunteers from the first “mechanism validation” phase II clinical trial of a mutagenic base analog in which individuals previously treated with antiviral drugs received 1600 mg of KP1461 twice per day for 124 days. Plasma viral loads were not reduced, and overall levels of viral mutation were not increased during this short-term study, however, the mutation spectrum of HIV was altered. A large number (N = 105 per sample) of sequences were analyzed, each derived from individual HIV-1 RNA templates, after 0, 56 and 124 days of therapy from 10 treated and 10 untreated control individuals (>7.1 million base pairs of unique viral templates were sequenced). We found that private mutations, those not found in more than one viral sequence and likely to have occurred in the most recent rounds of replication, increased in treated individuals relative to controls after 56 (p = 0.038) and 124 (p = 0.002) days of drug treatment. The spectrum of mutations observed in the treated group showed an excess of A to G and G to A mutations (p = 0.01), and to a lesser extent T to C and C to T mutations (p = 0.09), as predicted by the mechanism of action of the drug. These results validate the proposed mechanism of action in humans and should spur development of this novel antiretroviral approach.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1371/journal.pone.0015135
