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 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.
Department of Microbiology, University of Washington, School of Medicine, Seattle, Washington, United States of America. jmullins@uw.edu
James I
JI
Mullins
Laura
L
Heath
James P
JP
Hughes
Jessica
J
Kicha
Sheila
S
Styrchak
Kim G
KG
Wong
Ushnal
U
Rao
Alexis
A
Hansen
Kevin S
KS
Harris
Jean-Pierre
JP
Laurent
Deyu
D
Li
Jeffrey H
JH
Simpson
John M
JM
Essigmann
Lawrence A
LA
Loeb
Jeffrey
J
Parkins
D019380:Anti-HIV Agents; D004252:DNA Mutational Analysis; D016679:Genome, Viral / Q000187:drug effects* / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009705:Nucleosides / Q000008:administration & dosage / Q000494:pharmacology*; D019562:Viral Load / Q000187:drug effects
D019380:Anti-HIV Agents; C522536:KP 1461; D009705:Nucleosides
Lancet Infect Dis. 2003 Jan;3(1):28-32
12505030
J Virol. 1990 Aug;64(8):3960-2
1695258
J Virol. 2007 Oct;81(20):11256-66
17686844
Biometrics. 2005 Mar;61(1):106-17
15737083
Curr Top Microbiol Immunol. 2006;299:1-31
16568894
Science. 1996 Jul 26;273(5274):415-6
8677432
J Infect Dis. 2006 Dec 15;194(12):1661-71
17109337
J Virol. 1999 Dec;73(12):10489-502
10559367
J Virol. 2003 Oct;77(20):11193-200
14512567
Ann Intern Med. 1996 Aug 15;125(4):257-64
8678387
Eur J Biochem. 1997 Dec 1;250(2):492-501
9428703
PLoS One. 2009 May 25;4(5):e5683
19479085
Virology. 2003 Jun 5;310(2):333-42
12781720
Bioinformatics. 2007 Sep 1;23(17):2334-6
17586542
Annu Rev Microbiol. 2004;58:183-205
15487935
J Virol. 2005 Aug;79(15):9625-34
16014925
Virus Res. 2005 Feb;107(2):129-39
15649559
PLoS Pathog. 2007 Aug 31;3(8):e122
17784786
AIDS. 2000 Jul 7;14(10):1357-63
10930150
Virus Res. 2005 Feb;107(2):215-28
15649567
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1492-7
9990051
Genetics. 1974 Oct;78(2):737-56
4448362
Virology. 2003 Jul 5;311(2):339-49
12842623
Curr Top Microbiol Immunol. 2006;299:171-92
16568899
J Virol. 2003 Jan;77(2):1092-104
12502825
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13374-6
12370416
JAMA. 1998 Jul 1;280(1):67-71
9660366
J Antimicrob Chemother. 2002 Sep;50(3):309-11
12205054
J Virol. 2003 May;77(10):5721-30
12719565
PLoS Pathog. 2010 Jul 22;6(7):e1001005
20661479
J Virol. 2002 Jan;76(2):707-16
11752161
Nat Med. 2008 Feb;14(2):154-61
18246077
PLoS Pathog. 2009 Nov;5(11):e1000658
19911056
Science. 1993 Mar 19;259(5102):1749-54
8096089
Virus Res. 2005 Feb;107(2):173-81
15649563
AIDS Res Hum Retroviruses. 1997 Jun 10;13(9):737-42
9171217
Antiviral Res. 2005 Jul;67(1):10-7
15950748
Biotechniques. 2010 May;48(5):405-8
20569214
J Virol. 2007 Nov;81(21):11722-9
17699579
Science. 1995 Jan 27;267(5197):483-9
7824947
J Virol. 2009 Nov;83(22):11950-8
19726509
Comput Appl Biosci. 1996 Dec;12(6):543-8
9021275
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6895-900
11371613
Antiviral Res. 2005 Jul;67(1):1-9
15890415
Naturwissenschaften. 1971 Oct;58(10):465-523
4942363
Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
15034147
Genetics. 2004 Aug;167(4):1573-83
15342499