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Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461.

Mullins JI, Heath L, Hughes JP, Kicha J, Styrchak S, Wong KG, Rao U, Hansen A, Harris KS, Laurent JP, Li D, Simpson JH, Essigmann JM, Loeb LA, Parkins J - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Washington, School of Medicine, Seattle, Washington, United States of America. jmullins@uw.edu

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.

Show MeSH
Genetic diversity of 1.0 kb segments of HIV-1 gag genes through time in individuals treated and untreated with KP1461.Average population diversity of samplings of 105 1.0 kb gag gene segments through time is shown for treated (panel A) and untreated (panel B) groups.
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pone-0015135-g002: Genetic diversity of 1.0 kb segments of HIV-1 gag genes through time in individuals treated and untreated with KP1461.Average population diversity of samplings of 105 1.0 kb gag gene segments through time is shown for treated (panel A) and untreated (panel B) groups.

Mentions: Viral diversity typically increases during asymptomatic HIV infection and then may decrease thereafter [26]. We did not observe a consistent trend in diversity in these subjects over the 125-day period of examination (Figure 2), perhaps due to the relatively short observation time, to obtaining sequences from a relatively conserved region of the HIV-1 genome, and by sampling individuals in varied disease states. Furthermore, by definition, viral genomes that develop lethal mutations would not reproduce and may be quickly lost from the viral population. Hence, to enhance the sensitivity of our analysis we focused on mutations that reflect the most recent rounds of replication, “private site mutations”, defined as a mutation found in only one of the (N = 105) viral genomes sequenced. As shown in Figure 3, a substantial increase in private site mutations was noted in these subjects (Figure 3A), especially over the first 56 days of treatment (Figure 3B, p = 0.038).


Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461.

Mullins JI, Heath L, Hughes JP, Kicha J, Styrchak S, Wong KG, Rao U, Hansen A, Harris KS, Laurent JP, Li D, Simpson JH, Essigmann JM, Loeb LA, Parkins J - PLoS ONE (2011)

Genetic diversity of 1.0 kb segments of HIV-1 gag genes through time in individuals treated and untreated with KP1461.Average population diversity of samplings of 105 1.0 kb gag gene segments through time is shown for treated (panel A) and untreated (panel B) groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3021505&req=5

pone-0015135-g002: Genetic diversity of 1.0 kb segments of HIV-1 gag genes through time in individuals treated and untreated with KP1461.Average population diversity of samplings of 105 1.0 kb gag gene segments through time is shown for treated (panel A) and untreated (panel B) groups.
Mentions: Viral diversity typically increases during asymptomatic HIV infection and then may decrease thereafter [26]. We did not observe a consistent trend in diversity in these subjects over the 125-day period of examination (Figure 2), perhaps due to the relatively short observation time, to obtaining sequences from a relatively conserved region of the HIV-1 genome, and by sampling individuals in varied disease states. Furthermore, by definition, viral genomes that develop lethal mutations would not reproduce and may be quickly lost from the viral population. Hence, to enhance the sensitivity of our analysis we focused on mutations that reflect the most recent rounds of replication, “private site mutations”, defined as a mutation found in only one of the (N = 105) viral genomes sequenced. As shown in Figure 3, a substantial increase in private site mutations was noted in these subjects (Figure 3A), especially over the first 56 days of treatment (Figure 3B, p = 0.038).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Washington, School of Medicine, Seattle, Washington, United States of America. jmullins@uw.edu

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.

Show MeSH