HIV-1 Vpr protein impairs lysosome clearance causing SNCA/alpha-synuclein accumulation in neurons

Santerre, Maryline; Arjona, Sterling P.; Allen, Charles N. S.; Callen, Shannon; Buch, Shilpa; Sawaya, Bassel E.

doi:10.1080/15548627.2021.1915641

Cited by 24 publications

(15 citation statements)

References 78 publications

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“…Viruses also cause changes in metabolism, mitochondrial shape, and size [ 159 ]. The HIV-1 Vpr alters mitochondrial cristae, which results in mitochondrial swelling and irregular shape [ 160 ]. A similar effect was observed in cells infected with SARS-CoV-2 [ 161 ].…”

Section: Viruses and Mitochondrial Changes And Tca Cycle Rewiringmentioning

confidence: 99%

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

Allen

Arjona

Santerre

et al. 2022

Viruses

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Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.

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Section: Viruses and Mitochondrial Changes And Tca Cycle Rewiringmentioning

confidence: 99%

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

Allen

Arjona

Santerre

et al. 2022

Viruses

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“…Studies revealed the presence of viral proteins like gp120 in the cerebrospinal fluid (CSF) of infected patients ( Desplats et al, 2013 ). Studies also described the neuronal damage caused by these viral proteins ( Santerre et al, 2019 , 2021 ; Speidell et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Allen

Arjona

Santerre

et al. 2022

Front. Cell. Neurosci.

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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. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and 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 brain-derived neurotrophic factor (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 the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.

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“…Taken together, our findings suggest that MPA enhances HIV intracellular accumulation and extracellular release by inhibiting lysosomal activity. Several studies have revealed the association of lysosomal activity with HIV-1 pathogenesis [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]. While these reports agree that inhibiting lysosomal activity would increase HIV-1 infectivity, whether lysosomal activity would affect viral release remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone Acetate (MPA) Enhances HIV-1 Accumulation and Release in Primary Cervical Epithelial Cells by Inhibiting Lysosomal Activity

et al. 2021

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Medroxyprogesterone acetate (MPA) is one of the most widely used contraceptives in the world. Epidemiologic studies have uncovered a possible link between the use of MPA and an increased risk of HIV-1 transmission. However, the understanding of the mechanism is still limited. Our previous publication demonstrated that the lysosomal activity in human vaginal epithelial cells attenuated the trafficking of viral particles during HIV-1 transcytosis. In this study, we show that treating human primary cervical epithelial cells with MPA led to a reduction in lysosomal activity. This reduction caused an increase in the intracellular HIV-1 accumulation and, consequently, an increase in viral release. Our study uncovers a novel mechanism by which MPA enhances HIV-1 release in primary cervical epithelial cells, thus providing vital information for HIV intervention and prevention.

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HIV-1 Vpr protein impairs lysosome clearance causing SNCA/alpha-synuclein accumulation in neurons

Cited by 24 publications

References 78 publications

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Medroxyprogesterone Acetate (MPA) Enhances HIV-1 Accumulation and Release in Primary Cervical Epithelial Cells by Inhibiting Lysosomal Activity

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