Age-Dependent Alterations In Neuroimmune Signaling And Cognitive Vulnerability In HIV-1–Infected Humanized Mice

Aging is a critical modifier of HIV-1–associated neuroimmune dysfunction, yet the mechanisms linking immune activation, neural injury, and functional vulnerability remain incompletely defined. This study investigated age-dependent neuroimmune alterations in HIV-1–infected humanized mice using integrated molecular, cellular, and behavioral assessments. A total of 60 humanized NOD/SCID/IL2Rγ-null mice were stratified into young (12–16 weeks) and aged (36–40 weeks) cohorts prior to HIV-1 infection and monitored for 20 weeks under suppressive antiretroviral therapy. Neuroinflammation was quantified by measuring human cytokine and chemokine profiles in brain tissue and cerebrospinal fluid using multiplex immunoassays, while microglial activation and synaptic integrity were evaluated through immunofluorescence and confocal microscopy. Cognitive and motor performance were assessed using novel object recognition and open-field tests. Compared with younger counterparts, aged HIV-1–infected mice exhibited significantly elevated levels of TNF-α, IL-6, and CCL2 in the brain (1.8–2.6-fold increase, p<0.01), accompanied by a 34% reduction in synaptophysin-positive synaptic density. Behavioral testing revealed a 29% decline in recognition index and increased locomotor variability in aged infected mice, despite comparable plasma viral suppression across age groups. Correlation analysis demonstrated that neuroinflammatory markers explained 47% of the variance in cognitive impairment independent of peripheral viral load. These findings indicate that aging amplifies neuroimmune dysregulation and functional vulnerability in HIV-1 infection, highlighting the need for age-sensitive strategies when evaluating neuroprotective interventions in HIV-associated neurological disease.