6th Edition of Neurology World Conference 2026

Abstract

Despite virologic suppression on ART, people living with HIV (PLWH) are at high risk of age-related diseases and accelerated aging. However, the underlying mechanisms contributing to this increased risk have not been completely defined but may include genomic and epigenetic changes, cellular senescence, mitochondrial dysfunction, and metabolic alterations. We utilized CD34-NSG humanized mice, which supports long-term systemic engraftments of a functional human immune system to investigate aging-associated signaling pathways in late-stage of HIV-1 infection. CD34-NSG humanized mice were infected with HIV-1ADA at 20 weeks of age following humanization and maintained for an additional 40 weeks. Immune and viral profiles were analyzed at 0, 4-, 8-, 16- and 40 weeks post-infection. At 60 weeks of age, mice were sacrificed, and brains were isolated to evaluate the viral expression and key aging markers utilizing RT qPCR, immunofluorescence, and transcriptomic assays. A gradual decline of the CD4+ T cells and steady viral replication were observed in infected aged mice at the endpoint. Transcriptomic analysis of infected aged brains demonstrated an overall downregulation of the genes involved in human aging. The top 4 differentially expressed genes are COL1A, ELP3, LMNA, and SIRT1. Ingenuity pathway analysis further revealed several major pathways affected in HIV-infected aged mice were related to neutrophil activity, pyroptosis, phagosome formation, and Granzyme A and LXR/RXR signaling. The transcriptomics data corroborated with the immunofluorescence data for neuronal and non-neuronal markers in several brain compartments.

To summarize, CD34-NSG humanized mice can be used as a model system to study HIV-associated aging. Upregulation of immune-senescence-associated and downregulation of major signaling pathways was observed in HIV-1 infected aged mice. To explore the underlying mechanisms that may contribute to the increased prevalence of age-related comorbidities in PLWH under ART treatment, it is necessary to identify HIV-aging-related biomarkers, which will help to design appropriate intervention strategies for clinical translation.