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Sequence editing by Apolipoprotein B RNA-editing catalytic component [corrected] and epidemiological surveillance of transmitted HIV-1 drug resistance.

ABSTRACT: 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.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.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.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.

SUBMITTER: Gifford RJ

PROVIDER: S-EPMC2946849 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Sequence editing by Apolipoprotein B RNA-editing catalytic component [corrected] and epidemiological surveillance of transmitted HIV-1 drug resistance.

Gifford Robert J RJ Rhee Soo-Yon SY Eriksson Nicolas N Liu Tommy F TF Kiuchi Mark M Das Amar K AK Shafer Robert W RW

AIDS (London, England) 20080301 6

<h4>Design</h4>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.<h4>Methods</h4>Classifiers of lethal, APOBEC-mediated editing were developed by analysis of lentiviral pol gene sequence v ...[more]

PMID: 18356601

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Project description:IntroductionHIV-1 transmitted drug resistance (TDR) prevalence increased during the initial years of the antiretroviral therapy (ART) global scale-up. Few studies have examined recent trends in TDR prevalence using published genetic sequences and described the characteristics of ART-naïve persons from whom these published sequences have been obtained.MethodsWe identified 125 studies published between 2014 and 2019 for which HIV-1 reverse transcriptase (RT) with or without protease from ≥50 ART-naïve adult persons were submitted to the GenBank sequence database. The population characteristics and TDR prevalence were compared to those in 122 studies published in the preceding five years between 2009 and 2013. TDR prevalence was analysed using median study-level and person-level data.Results and discussionThe 2009 to 2013 and 2014 to 2019 studies reported sequence data from 32,866 and 41,724 ART-naïve persons respectively. Studies from the low- and middle-income country (LMIC) regions in sub-Saharan Africa, South/Southeast Asia and Latin America/Caribbean accounted for approximately two-thirds of the studies during each period. Between the two periods, the proportion of studies from sub-Saharan Africa and from South/Southeast Asia countries other than China decreased from 43% to 32% and the proportion of studies performed at sentinel sites for recent HIV-1 infection decreased from 33% to 22%. Between 2014 and 2019, median study-level TDR prevalence was 4.1% in South/Southeast Asia, 6.0% in sub-Saharan Africa, 9.1% in Latin America/Caribbean, 8.5% in Europe and 14.2% in North America. In the person-level analysis, there was an increase in overall, NNRTI and two-class NRTI/NNRTI resistance in sub-Saharan Africa; an increase in NNRTI resistance in Latin America/Caribbean, and an increase in overall, NNRTI and PI resistance in North America.ConclusionsOverall, NNRTI and dual NRTI/NNRTI-associated TDR prevalence was significantly higher in sub-Saharan Africa studies published between 2014 and 2019 compared with those published between 2009 and 2013. The decreasing proportion of studies from the hardest hit LMIC regions and the shift away from sentinel sites for recent infection suggests that global TDR surveillance efforts and publication of findings require renewed emphasis.

Project description:A population of human immunodeficiency virus (HIV) within a host often descends from a single transmitted/founder virus. The high mutation rate of HIV, coupled with long delays between infection and diagnosis, make isolating and characterizing this strain a challenge. In theory, ancestral reconstruction could be used to recover this strain from sequences sampled in chronic infection; however, the accuracy of phylogenetic techniques in this context is unknown. To evaluate the accuracy of these methods, we applied ancestral reconstruction to a large panel of published longitudinal clonal and/or single-genome-amplification HIV sequence data sets with at least one intrapatient sequence set sampled within 6 months of infection or seroconversion (n = 19,486 sequences, median [interquartile range] = 49 [20 to 86] sequences/set). The consensus of the earliest sequences was used as the best possible estimate of the transmitted/founder. These sequences were compared to ancestral reconstructions from sequences sampled at later time points using both phylogenetic and phylogeny-naive methods. Overall, phylogenetic methods conferred a 16% improvement in reproducing the consensus of early sequences, compared to phylogeny-naive methods. This relative advantage increased with intrapatient sequence diversity (P < 10(-5)) and the time elapsed between the earliest and subsequent samples (P < 10(-5)). However, neither approach performed well for reconstructing ancestral indel variation, especially within indel-rich regions of the HIV genome. Although further improvements are needed, our results indicate that phylogenetic methods for ancestral reconstruction significantly outperform phylogeny-naive alternatives, and we identify experimental conditions and study designs that can enhance accuracy of transmitted/founder virus reconstruction.When HIV is transmitted into a new host, most of the viruses fail to infect host cells. Consequently, an HIV infection tends to be descended from a single "founder" virus. A priority target for the vaccine research, these transmitted/founder viruses are difficult to isolate since newly infected individuals are often unaware of their status for months or years, by which time the virus population has evolved substantially. Here, we report on the potential use of evolutionary methods to reconstruct the genetic sequence of the transmitted/founder virus from its descendants at later stages of an infection. These methods can recover this ancestral sequence with an overall error rate of about 2.3%-about 15% more information than if we had ignored the evolutionary relationships among viruses. Although there is no substitute for sampling infections at earlier points in time, these methods can provide useful information about the genetic makeup of transmitted/founder HIV.

Dataset Information

Sequence editing by Apolipoprotein B RNA-editing catalytic component [corrected] and epidemiological surveillance of transmitted HIV-1 drug resistance.

Publications

Sequence editing by Apolipoprotein B RNA-editing catalytic component [corrected] and epidemiological surveillance of transmitted HIV-1 drug resistance.

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