Residual HIV activity and host immunometabolic remodeling during antiretroviral therapy: implications for...

Antiretroviral therapy (ART) suppresses productive HIV replication but does not eliminate viral persistence, residual transcription, or host immune perturbation. Low-level viremia (LLV), generally referring to detectable plasma HIV RNA below the threshold for virologic failure, has traditionally been interpreted in relation to assay variability, incomplete ART exposure, resistance, or impending rebound. Persistent or recurrent LLV may signal residual HIV activity or residual antigenic exposure, but it is not a direct measure of these processes and should not be equated with ongoing productive replication. Residual viral and antigenic signals may interact with microbial, metabolic, behavioral, adiposity-related, and treatment-related inputs, potentially contributing to trained-immunity-like programs, T-cell dysfunction, mitochondrial dysfunction, redox imbalance, impaired lipid handling, and broader immunometabolic perturbation. We therefore position persistent or recurrent LLV as a pattern-dependent virologic phenotype to be interpreted alongside direct measures of residual HIV activity, host immunometabolic phenotypes, contextual determinants, and established cardiovascular-kidney-metabolic (CKM) risk factors. The CKM framework organizes interrelated metabolic, vascular, and kidney-related vulnerability; it does not define an HIV-specific staging system or position LLV as a cause or staging criterion for CKM syndrome. Future studies are needed to define biologically informative LLV patterns, establish the temporal relationships between accompanying host signatures and CKM-related outcomes, and determine whether such patterns and signatures provide clinically meaningful information beyond established treatment-related and CKM risk factors.