This study used a novel humanized APP knock-in mouse model (hNAIL) — carrying the Swedish familial AD mutation on an immunodeficient NOG background with human microglia-like cells — to examine how sustained brain HIV-1 replication (HIV-1ADA strain, 8 weeks post-infection) affects early Alzheimer's-like pathology, including amyloid burden, synaptic integrity, neuroinflammation, and transcriptional changes (n=7–9 per group, 4 groups).
HIV-1 infection significantly increased soluble and insoluble Aβ42 in hippocampus and cortex, reduced postsynaptic PSD-95 and neuronal markers (MAP2, NeuN), caused ~4-fold microglial activation vs. controls (vs. ~2-fold with amyloid alone), and produced cortical atrophy on MRI at 6 months. Spatial transcriptomics showed dual Aβ+HIV-1 pathology amplified transcriptional injury beyond either alone, with neurons showing the highest response (1,646 DEGs vs. 419 in astrocytes and 489 in microglia), and reduced Aβ-degrading enzymes IDE and neprilysin in infected mice.
- The immunodeficient NOG background impairs baseline cognition, limiting detection of additional HIV-1-induced cognitive deficits. - Only untreated HIV-1 infection was studied; ART-treated conditions (more clinically relevant) were not evaluated. - The model produces predominantly intraneuronal Aβ without extracellular plaques or tau pathology, limiting generalizability to late-stage AD.
Clinicians managing aging PLWH should be aware that HIV-1 brain replication may accelerate early Alzheimer's-like amyloid accumulation and neuronal injury through impaired Aβ clearance, supporting closer cognitive monitoring and motivating trials of ART regimens that penetrate the CNS.
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