Deconvolution of HIV-1 Mutational Signatures Reveals Dominant and Donor-Specific APOBEC3-Associated Mutagenesis Across Anatomical Compartments

Authors

Soleimanpour, M., Haghjoo, N., lehle, J., Springman-Rodriguez, R., M. Smith, D., Gianella Weibel, S., Chaillon, A., Ebrahimi, D.

Abstract

HIV-1 persists across multiple anatomical compartments, yet the mutational processes shaping viral diversity within these reservoirs remain incompletely understood. We investigated HIV-1 mutational signatures across blood, spleen, gut, and brain tissues from 21 people with HIV enrolled in the Last Gift rapid autopsy program. Mutations in single-genome HIV-1 env DNA sequences were quantified by trinucleotide context and deconvolved using non-negative matrix factorization. Two APOBEC3-associated signatures were resolved and together accounted for approximately 50% of all mutations; this contribution remained stable after normalization by the number of potential APOBEC3 target sites. Normalization further revealed a minor signature consistent with methylation-induced cytosine deamination. Mutational patterns were driven primarily by donor identity rather than anatomical compartment. Identical APOBEC3-hypermutated sequences were recovered across brain, gut, and blood, consistent with clonal expansion and trafficking of infected cells. These findings establish APOBEC3 activity as a major contributor to HIV-1 mutagenesis across tissue reservoirs and demonstrate that APOBEC3-associated mutagenesis is strongly donor-specific.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 26 Sep 2026.

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