Sequence editing by Apolipoprotein B RNA-editing catalytic component [corrected] and epidemiological surveillance of transmitted HIV-1 drug resistance.
METHODS
Promiscuous guanine (G) to adenine (A) substitutions catalysed by apolipoprotein B RNA-editing catalytic component (APOBEC) enzymes are observed in a proportion of HIV-1 sequences in vivo and can introduce artifacts into some genetic analyses. The potential impact of undetected lethal editing on genotypic estimation of transmitted drug resistance was assessed.


METHODS
Classifiers of lethal, APOBEC-mediated editing were developed by analysis of lentiviral pol gene sequence variation and evaluated using control sets of HIV-1 sequences. The potential impact of sequence editing on genotypic estimation of drug resistance was assessed in sets of sequences obtained from 77 studies of 25 or more therapy-naive individuals, using mixture modelling approaches to determine the maximum likelihood classification of sequences as lethally edited as opposed to viable.


RESULTS
Analysis of 6437 protease and reverse transcriptase sequences from therapy-naive individuals using a novel classifier of lethal, APOBEC3G-mediated sequence editing, the polypeptide-like 3G (APOBEC3G)-mediated defectives (A3GD) index', detected lethal editing in association with spurious 'transmitted drug resistance' in nearly 3% of proviral sequences obtained from whole blood and 0.2% of samples obtained from plasma.


CONCLUSIONS
Screening for lethally edited sequences in datasets containing a proportion of proviral DNA, such as those likely to be obtained for epidemiological surveillance of transmitted drug resistance in the developing world, can eliminate rare but potentially significant errors in genotypic estimation of transmitted drug resistance.
Gifford
Robert J
RJ
Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California 94305, USA. rjmg@stanford.edu
Rhee
Soo-Yon
SY
Eriksson
Nicolas
N
Liu
Tommy F
TF
Kiuchi
Mark
M
Das
Amar K
AK
Shafer
Robert W
RW
D000071479:APOBEC-1 Deaminase; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics*; D030541:Databases, Genetic; D003906:Developing Countries; D024921:Drug Resistance, Multiple, Viral; D019450:Genes, MDR; D005814:Genes, Viral; D005838:Genotype; D015658:HIV Infections / Q000175:diagnosis / Q000635:transmission*; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D017393:RNA Editing; D012372:ROC Curve; D017422:Sequence Analysis, DNA
D054303:HIV Reverse Transcriptase; D016333:HIV Protease; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; D003564:Cytidine Deaminase