Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders (HAND)

Abstract

A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. However, the exact mechanisms that causes these changes that are observed to lead to memory dysfunction have yet to be elucidated. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, we have shown that gp120 decreases mitochondrial oxygen consumption rate (OCR) and increases the expression of polypyrimidine tract binding protein 1 (PTBP1), resulting in the alternative splicing of pyruvate kinase M (PKM) from PKM1 to PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature BDNF. The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within promoter regions. One of the more important promoters that ICER binds to is the BDNF promoters II and IV, thus altering normal synaptic plasticity. We also validated these results in an animal model. We have also shown that with the addition of a therapeutic drug, Tepp-46, which promotes PKM2 tetramers, the metaboliciv changes in glycolysis and subsequential accumulation of AGEs can be reversed. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients, as well as a possible therapeutic target to aid in the prevention of metabolic reprogramming and the progression of HAND.