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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2011-1-25
pubmed:abstractText
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.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-10559367, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-10930150, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-11752161, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-12205054, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-12370416, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-12502825, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-12505030, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-12719565, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-12781720, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-12842623, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-14512567, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15034147, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15342499, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15487935, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15649559, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15649563, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15649567, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15737083, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15890415, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-15950748, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-16014925, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-16568894, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-16568899, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-1695258, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-17109337, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-17586542, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-17686844, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-17699579, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-17784786, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-18246077, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-19479085, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-19726509, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-19911056, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-20569214, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-20661479, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-4448362, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-4942363, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-7824947, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-8096089, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-8677432, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-8678387, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-9021275, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-9171217, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-9428703, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-9660366, http://linkedlifedata.com/resource/pubmed/commentcorrection/21264288-9990051
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1932-6203
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
6
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
e15135
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461.
pubmed:affiliation
Department of Microbiology, University of Washington, School of Medicine, Seattle, Washington, United States of America. jmullins@uw.edu
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