HIV, ART and aging: Role of Lactate in NeuroHIV

About This Grant

PROJECT SUMMARY/ABSTRACT People living with HIV (PLWH) in the current era of effective combination antiretroviral therapy (cART) experience significant burdens as a result of HIV-related neurocognitive disorders (HAND/NeuroHIV). This is partially due to cART’s impact on the lifespan of PLWH, as they now live longer with co-morbidities such as aging. Our preliminary studies show enhanced lactylation has been observed in younger SIV-infected nonhuman primates (NHPs) compared to older ones and in SIV-infected NHPs on ART. This suggests that lactate may play a critical role in contributing to the pathogenesis and progression of HAND. Extant research shows that metabolites from glycolysis and the tricarboxylic (TCA) cycle, particularly lactate, play crucial roles in post-translational modifications like histone lactylation, which can regulate gene expression and stimulate inflammatory pathways. Additionally, studies show SIV infection in NHPs causes gut microbiome dysbiosis of lactate metabolizing species such as Lactobacillus and also that HIV protein Tat down-regulates lactate production in astrocytes, while microRNA-29b may regulate lactate metabolism and contribute to HAND progression, underscoring the need for further investigation into these mechanisms. We hypothesize that age, premature aging, and lactate-mediated lactylation play a significant role in developing and progressing HAND/NeuroHIV in PLWH. In Aim 1, we will use an NHP model of SIV infection with ART to test this hypothesis by examining lactate levels in plasma and CSF, as well as MRI scans to assess spatial memory of two groups of rhesus macaques (one young, one old) until necropsy. At necropsy, changes in lactylation levels and synaptodendritic injury in the prefrontal cortex and temporal lobe will be analyzed using immunohistochemistry and global proteomics. In Aim 2, we will use the same study design as Aim 1 and treat a subset of both groups with probiotics three months before necropsy to identify the effect of probiotic-derived lactate in HAND progression. In Aim 3, we will examine how microRNA- 29b impacts the regulation of lactate production in human iPSC-derived astrocytes, microglia, and neurons using extracellular vesicles (EVs) isolated from Tat-treated astrocytes and HIV-1 infected microglia to analyze lactate production and its impact on neuronal survival and neuronal metabolism using SeaHorse technology. The proposed studies aim to investigate the interplay between aging, lactate-mediated lactylation, and the progression of HAND in PLWH. Our long-term objective is to identify novel therapeutic strategies to mitigate HAND, an untreatable condition significantly impacting this population's neurological health. We will integrate metabolic profiling, proteomics, histological techniques, and advanced imaging to comprehensively assess the mechanisms underlying HAND and the potential therapeutic benefits of lactate modulation for PLWH. Successful completion of this work could lead to innovative strategies that enhance metabolic health and neurological outcomes for PLWH, improving their overall quality of life.