Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461
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 infe...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2011
|
| Online Access: | http://hdl.handle.net/1721.1/65401 https://orcid.org/0000-0002-2196-5691 |
| _version_ | 1811080711653818368 |
|---|---|
| author | 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 Li, Deyu Simpson, Jeffrey H. Essigmann, John M. Loeb, Lawrence A. Parkins, Jeffrey |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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 Li, Deyu Simpson, Jeffrey H. Essigmann, John M. Loeb, Lawrence A. Parkins, Jeffrey |
| author_sort | Mullins, James I. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:35:34Z |
| format | Article |
| id | mit-1721.1/65401 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:35:34Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/654012022-10-01T04:37:36Z Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461 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 Li, Deyu Simpson, Jeffrey H. Essigmann, John M. Loeb, Lawrence A. Parkins, Jeffrey Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Essigmann, John M. Li, Deyu Simpson, Jeffrey H. Essigmann, John M. 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. Koronis Pharmaceuticals 2011-08-26T15:25:20Z 2011-08-26T15:25:20Z 2011-01 2010-08 Article http://purl.org/eprint/type/JournalArticle http://hdl.handle.net/1721.1/65401 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. https://orcid.org/0000-0002-2196-5691 en_US http://dx.doi.org/10.1371/journal.pone.0015135 PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | 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 Li, Deyu Simpson, Jeffrey H. Essigmann, John M. Loeb, Lawrence A. Parkins, Jeffrey Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461 |
| title | Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461 |
| title_full | Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461 |
| title_fullStr | Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461 |
| title_full_unstemmed | Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461 |
| title_short | Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461 |
| title_sort | mutation of hiv 1 genomes in a clinical population treated with the mutagenic nucleoside kp1461 |
| url | http://hdl.handle.net/1721.1/65401 https://orcid.org/0000-0002-2196-5691 |
| work_keys_str_mv | AT mullinsjamesi mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT heathlaura mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT hughesjamesp mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT kichajessica mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT styrchaksheila mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT wongkimg mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT raoushnal mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT hansenalexis mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT harriskevins mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT laurentjeanpierre mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT lideyu mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT simpsonjeffreyh mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT essigmannjohnm mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT loeblawrencea mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 AT parkinsjeffrey mutationofhiv1genomesinaclinicalpopulationtreatedwiththemutagenicnucleosidekp1461 |