Deconvolution of HIV-1 Mutational Signatures Reveals Dominant and Donor-Specific APOBEC3-Associated Mutagenesis Across Anatomical Compartments
- 1Texas Biomedical Research Institute
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.
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BibTeX
@misc{soleimanpour2026deconvolution,
title = {{Deconvolution of HIV-1 Mutational Signatures Reveals Dominant and Donor-Specific APOBEC3-Associated Mutagenesis Across Anatomical Compartments}},
author = {M. Soleimanpour and N. Haghjoo and J. lehle and R. Springman-Rodriguez and D. M. Smith and S. Gianella Weibel and A. Chaillon and D. Ebrahimi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753842},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753842v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Deconvolution of HIV-1 Mutational Signatures Reveals Dominant and Donor-Specific APOBEC3-Associated Mutagenesis Across Anatomical Compartments
AU - M. Soleimanpour
AU - N. Haghjoo
AU - J. lehle
AU - R. Springman-Rodriguez
AU - D. M. Smith
AU - S. Gianella Weibel
AU - A. Chaillon
AU - D. Ebrahimi
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753842
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753842v1
AB - 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.
ER -