title: Estimating the relative contribution of dNTP pool imbalance and APOBEC3G/3F editing to HIV evolution in vivo.
abstract: The human immunodeficiency virus (HIV) has a genome that is rich in adenine, and its rapid evolution shows an observed bias of guanine (G) to adenine (A) mutations. Two mechanisms have been proposed to explain these properties: (1) an imbalance in dNTP pool concentrations which drives the misincorporation process during reverse transcription, and (2) cytidine deamination by the APOBEC3G/3F restriction factor, causing G to A mutations most notably in specific dinucleotide contexts. Although crucial to understanding HIV evolution, current estimates on misincorporation bias during the replication cycle are based on scarce in vitro measurements. In this work, HIV partial pol sequences obtained for drug resistance testing purposes are analyzed using likelihood methods to estimate various models of HIV misincorporation bias in vivo. The technique is robust to selection on the amino acid sequence and selection against CpG dinucleotides. A model where misincorporations are explained only by an imbalance in dNTP pool concentrations, together with a preference for transitions versus transversions, explained 98% (95% confidence interval [C.I.] 93-100) of the observed variation in freely estimated misincorporation rates. Although dinucleotide context was responsible for variation in misincorporation probabilities, this variation was not specific for G to A mutations implying that the footprint of APOBEC3G/3F editing could not be detected. These results indicate that an imbalance in dNTP pool concentrations explains most of the bias in HIV nucleotide misincorporations, while the effect of editing by APOBEC3G/3F on HIV evolution, based on its dinucleotide specificity, could not be observed in this study.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. koen.deforche@uz.kuleuven.ac.be
authors.forename: Koen
authors.initials: K
authors.lastname: Deforche
authors.forename: Ricardo
authors.initials: R
authors.lastname: Camacho
authors.forename: Kristel Van
authors.initials: KV
authors.lastname: Laethem
authors.forename: Beth
authors.initials: B
authors.lastname: Shapiro
authors.forename: Yves
authors.initials: Y
authors.lastname: Moreau
authors.forename: Andrew
authors.initials: A
authors.lastname: Rambaut
authors.forename: Anne-Mieke
authors.initials: AM
authors.lastname: Vandamme
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemey
mesh_terms: D000071480:APOBEC-3G Deaminase; D000465:Algorithms; D019295:Computational Biology; D003564:Cytidine Deaminase / Q000378:metabolism*; D043525:Cytosine Deaminase / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism*; D019143:Evolution, Molecular; D006678:HIV / Q000235:genetics* / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D006801:Humans; D016013:Likelihood Functions; D008390:Markov Chains; D008954:Models, Biological; D009010:Monte Carlo Method; D009154:Mutation; D017393:RNA Editing
chemical_list: D004279:DNA, Viral; D003854:Deoxyribonucleotides; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase