Reading immune restoration through Mycobacterium tuberculosis intrahost evolution

Antiretroviral therapy (ART) suppresses human immunodeficiency virus replication, but does not fully restore protection against tuberculosis. The relevant mechanisms are still poorly understood. M. C. Chao, M. R. Chase, S. Wakabayashi, A. J. Vickers, et al. (mSystems 11:e00329-26, 2026, https://doi.org/10.1128/msystems.00329-26) use population-level Mycobacterium tuberculosis genome sequencing in macaques to show that similar bacterial burdens can conceal different evolutionary trajectories: simian immunodeficiency virus coinfection primarily increases opportunities for mutation through replication, whereas ART-treated animals show a distinct enrichment of oxidative damage-associated variants. We argue that the principal value of this work is conceptual. Pathogen genomes may provide a time-integrated, but indirect, readout of local immune ecology. To translate these genomic signatures into a framework for evaluating immune restoration, future studies should pair host and pathogen measurements, experimentally validate the mechanisms generating these mutations, and longitudinally link tissue-level selection to persistence, reactivation, and transmission.