We find that people with non-suppressible human immunodeficiency virus (HIV) viremia despite antiretroviral therapy (ART) exhibit several distinguishing features. These include expanded CD4+ T cell clones containing HIV proviruses integrated into transcriptionally permissive regions, the presence of certain proviral defects or human leukocyte antigen (HLA)-escape mutations, enhanced survival signatures, and muted interferon and cytotoxic CD8+ T cell responses.