HIV-1 APOBEC-context mutations detected by next-generation sequencing in plasma: implications for drug resistance interpretation

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ID: 316075
2026
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Abstract
BACKGROUND & AIMS: APOBEC3-mediated cytidine deamination produces characteristic G→A substitutions in HIV genomes, classically described in proviral DNA but also detectable in plasma HIV-1 RNA using next-generation sequencing (NGS). APOBEC-signature mutations reflect enrichment of G→A substitutions in APOBEC target motifs, whereas APOBEC-context mutations correspond to substitutions at drug resistance-associated positions compatible with APOBEC editing. We evaluated their prevalence and implications for resistance interpretation in plasma NGS sequences. METHODS: We performed a retrospective multicentre analysis of plasma HIV-1 NGS-sequences from antiretroviral-naïve individuals in the period 2022-2023. Sequencing was performed in participating laboratories, and FASTQ files were centrally reanalysed using DeepChek. APOBEC-signature mutations, APOBEC-context drug resistance mutations (DRMs), and stop codons were evaluated across protease, reverse transcriptase, and integrase. Variant frequencies were analysed using thresholds of 1%, 3%, and 5%. RESULTS: Among 290 individuals, 268 had complete NGS data. At a 1% threshold, APOBEC-signature mutations were detected in 159 individuals and APOBEC-context DRMs in 64 (22%). The coexistence of both patterns was observed in 52 individuals (18%), decreasing to 17 (6%) and 8 (3%) at 3% and 5% thresholds, respectively. Certain mutations, including M184I, G190E, G140S, and R263K, remained detectable at higher thresholds. Integrase mutation R263K frequently co-occurred with multiple APOBEC-signature mutations and stop codons, consistent with extensive APOBEC-mediated editing. CONCLUSIONS: APOBEC-associated mutational patterns can be detected in plasma HIV-1 RNA by NGS and may affect interpretation of resistance results. Conservative frequency thresholds (5%) and evaluation of APOBEC signatures may help reduce misclassification of APOBEC-induced variants as clinically relevant resistance.
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openalex_W7163636295 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Marta Illescas-López, Paloma Muñoz, Adolfo de Salazar, Rafael Delgado, Asunción Iborra, Juan Carlos Galán, Raquel Carracedo, Mayra Sigcha, Carla López-Causapé, Ana Fuentes, Antonio Aguilera, Cristina Marco‐Sánchez, Féderico García
Journal The Journal of infectious diseases
Year 2026
DOI
10.1093/infdis/jiag277
URL
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