Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Area of Science:

• Neuroscience
• Molecular Biology
• Virology

Background:

• HIV-associated neurocognitive disorders (HAND), including spatial memory impairments and learning disabilities (SMI-LD), affect many HIV-1 patients.
• SMI-LD is also prevalent in patients undergoing combination antiretroviral therapy (cART).
• The HIV-1 gp120 protein has been implicated in promoting SMI-LD by disrupting mitochondrial function and energy production.

Purpose of the Study:

• To investigate the upstream cellular processes affected by gp120, specifically metabolic reprogramming.
• To elucidate the molecular mechanisms by which gp120 leads to HAND.
• To identify potential therapeutic targets for reversing gp120-induced neurotoxicity.

Main Methods:

• Neuronal cells were treated with the HIV-1 gp120 protein.
• Analysis of glycolysis pathway disruption, pyruvate kinase M (PKM) splicing, and protein expression (PTBP1, AGEs, pro-BDNF, BDNF, ICER).
• Assessment of synaptic plasticity alterations and reversal of effects using Tepp-46.

Main Results:

• Gp120 disrupted glycolysis at the pyruvate level and increased polypyrimidine tract binding protein 1 (PTBP1) expression.
• Increased PTBP1 led to PKM splicing into PKM1 and PKM2, resulting in advanced glycation end product (AGE) accumulation.
• Gp120 inhibited pro-BDNF cleavage to mature BDNF, leading to increased ICER expression, altered BDNF promoter activity, and impaired synaptic plasticity.

Conclusions:

• HIV-1 gp120 protein induces metabolic reprogramming in neuronal cells, contributing to HAND.
• The observed metabolic changes are linked to memory impairments and synaptic dysfunction.
• Stabilizing PKM2 with Tepp-46 reversed these detrimental effects, suggesting metabolic intervention as a therapeutic strategy for HAND.