Aging Reshapes Antiretroviral Handling in Tissue Compartments Relevant to HIV Persistence
Aging is changing the pharmacology of antiretroviral therapy in places that matter for HIV transmission, persistence, and long-term suppression. In a preprint built around proteomic analysis, investigators compared peripheral blood mononuclear cells and rectosigmoid colon tissue from younger HIV-seronegative adults, older HIV-seronegative adults, and older virally suppressed people living with HIV. The central finding was not a single pathway failure but a patterned remodeling of proteins tied to drug disposition, with age, HIV status, and sex exerting different effects across compartments.
The rectosigmoid signal deserves attention. This mucosal site sits at the intersection of exposure risk and viral persistence, yet most pharmacology discussions still default to blood. Here, aging produced broader changes in antiretroviral disposition-related proteins in rectosigmoid tissue than HIV status did, and those changes extended beyond classic transporters and metabolic enzymes. Proteins involved in drug transport, intracellular activation, dephosphorylation, and nucleotide homeostasis shifted with age, creating a biologic picture in which tissue-level handling of nucleos(t)ide reverse transcriptase inhibitors may evolve as people grow older.
Tissue-Specific Proteomics Point to NRTI Pathways as a Vulnerable Axis
The proteomic analysis centered on proteins and pathways relevant to antiretroviral disposition, and the strongest signals clustered in pathways tied to nucleos(t)ide reverse transcriptase inhibitors. That focus is clinically important because NRTIs rely on intracellular activation and balanced phosphorylation states to become pharmacologically active. If the enzymes and transport systems governing that process change with age, the effective drug exposure inside target tissues may diverge from what plasma concentrations suggest.
One sentence captures the problem starkly: blood does not necessarily tell the whole story for mucosal drug biology.
In rectosigmoid tissue, aging influenced a wider set of proteins than HIV infection itself, including components linked to drug transport, activation, and nucleotide regulation. Those findings fit a plausible mechanistic model. Mucosal tissue is metabolically active, exposed to local inflammatory cues, and structurally distinct from circulating immune cells. If nucleotide pools or phosphorylation enzymes shift with age, intracellular competition for active metabolites could change the local balance of antiviral pressure, especially in sites where HIV can establish or persist.
PBMCs Reflected HIV-Associated Effects More Than Aging Effects
The pattern in peripheral blood mononuclear cells looked different. HIV-associated changes in the proteome were more prominent in PBMCs than in rectosigmoid tissue, suggesting that circulating immune cells retain a stronger imprint of infection-related remodeling than the mucosal compartment does. That split matters because PBMCs are often used as convenient surrogate tissue in pharmacologic and virologic studies. Convenience, however, can obscure compartment-specific biology.
The data suggest two parallel processes. In blood cells, prior or ongoing HIV-related immune remodeling appears to dominate the proteomic signature. In rectosigmoid tissue, aging itself exerts a broader influence on the machinery that governs antiretroviral disposition. Those patterns are not interchangeable, and they likely reflect different cellular demands, tissue architectures, and exposure histories.
A single biomarker panel in blood will miss part of the story.
Sex Modulated Several Age-Associated Changes
Several age-associated alterations were further shaped by biologic sex, indicating that aging does not act uniformly across all adults. The preprint does not reduce sex to a background variable; instead, it places sex as a modifying factor in the molecular pathways that influence antiretroviral handling. That is biologically credible. Hormonal milieu, transporter expression, inflammatory tone, and mitochondrial activity can all differ by sex and may interact with aging to alter intracellular pharmacology.
This does not mean every sex-based difference will translate into a measurable dosing change, and the study does not claim that. It does mean that the same chronological age may not carry the same pharmacologic meaning in every patient. For clinicians, the implication is straightforward: older adults living with HIV may not share a single uniform disposition phenotype, even when virologic suppression is stable and treatment regimens are similar.
Nucleotide Homeostasis and Gut Function Broaden the Pharmacologic Frame
The pathway analyses reached beyond drug transport and metabolism. Aging was associated with alterations in pathways related to nucleotide metabolism and gastrointestinal tissue function, alongside immune regulation, cellular metabolism, and disease-associated programs. That breadth is telling. NRTI pharmacology depends on intracellular competition with endogenous nucleotides, so shifts in nucleotide homeostasis may directly influence the amount of active antiviral species that accumulates inside target cells.
The gastrointestinal component also matters. Rectosigmoid tissue is not just a passive reservoir; it is a biologically active mucosal environment with barrier functions, immune surveillance, and local metabolic demands. Changes in gut tissue programs can alter epithelial turnover, immune cell trafficking, and the local milieu that drugs must traverse before reaching intracellular targets. The result is a mechanistic framework in which age-related mucosal remodeling may influence antiretroviral exposure in ways that are invisible to standard plasma-based monitoring.
What the Preprint Can and Cannot Support
This work provides a mechanistic foundation, not a clinical endpoint. The preprint does not establish whether the proteomic shifts it observed translate into worse viral suppression, altered prophylaxis efficacy, or higher rates of resistance. It also does not measure actual intracellular drug concentrations, clinical outcomes, or long-term virologic consequences. Those gaps are substantial, and they should stay in view while the field interprets the findings.
Still, the biologic signal is coherent. Aging altered proteins tied to antiretroviral disposition in a tissue compartment central to HIV transmission and persistence, while HIV status left a stronger imprint in blood cells. Sex further modified selected age-related pathways. Together, these results argue that the pharmacology of ART in older adults may be shaped by tissue context as much as by regimen choice.
Future studies will need to connect this proteomic map to direct measurements of tissue drug exposure, intracellular activation, and antiviral effect in older adults living with HIV and in people using pre-exposure prophylaxis. Until then, the practical message is bounded but important: age-related changes in rectosigmoid biology may influence how antiretrovirals are handled where HIV matters most.