ArticleCell death & disease2017
HIV-1 Nef is released in extracellular vesicles derived from astrocytes: evidence for Nef-mediated neurotoxicity.
Article in Cell death & disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
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Who cites it
111 citing papers in PubMed, 132 citations in OpenAlex.
- Review
- HIV-1 Tat-driven Glutamate Dysregulation: Implications for Cognitive Impairment in HAND.Current HIV/AIDS reports · 2026Review
- HIV Reservoirs Across Multiple Tissues: From Heterogeneous Mechanisms to Therapeutic Targeting.Microorganisms · 2026Review
- Neuroinflammation and NeuroHIV: understanding the role of HIV-1 related factors in microglial activation.Translational psychiatry · 2026Review
- HIV-1 Nef induces astrocytes proliferation, inflammatory response, A1-like astrocytes polarization and subsequent neuronal apoptosis via NF-κB signaling pathway.Journal of neurovirology · 2026Article
- Altered neurovascular coupling in patients with human immunodeficiency virus-associated asymptomatic neurocognitive impairment: a multimodal magnetic resonance imaging study.Quantitative imaging in medicine and surgery · 2026Article
- A rest-task fMRI study of spatial working memory in HIV-infected individuals across cognitive states.BMC medical imaging · 2026Article
- Implications of virus-induced stress granules in tauopathies.Translational neurodegeneration · 2026Review
- SHIV.D Infection Alters Production and Protein Composition of Myeloid-Derived Extracellular Vesicles.International journal of molecular sciences · 2026Article
- Inflammatory microglia signals drive A1-like polarization of astrocytes even in the presence of HIV-1 Tat.Molecular neurobiology · 2025Article
- Multifaceted Role of Nef in HIV-Associated Neurocognitive Disorder: Histopathological Alterations and Underlying Mechanisms.Brain sciences · 2025Review
- Differential Effects of Human Immunodeficiency Virus Nef Variants on Pulmonary Vascular Endothelial Cell Dysfunction.Infectious disease reports · 2025Article
- Expression of HIV envelope protein in the human central nervous system.AIDS (London, England) · 2025Article
- Nef mediates neuroimmune response, myelin impairment, and neuronal injury in EcoHIV-infected mice.Life science alliance · 2025Article
- Astrocytic HIV-1 Nef Expression Decreases Glutamate Transporter Expression in the Nucleus Accumbens and Increases Cocaine-Seeking Behavior in Rats.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Nef is a key player in neuroinflammation and myelin impairment associated with neuroHIV.Frontiers in neurology · 2025Article
- Functional alteration of divided attention in people living with HIV based on a task-fMRI study.Frontiers in neuroscience · 2025Article
- HIV protein Nef expression in human microglia drives the release of distinct Nef-containing extracellular vesicles.Extracellular vesicles and circulating nucleic acids · 2025Article
- HIV-Associated Neurocognitive Disorder (HAND) and Alzheimer's Disease Pathogenesis: Future Directions for Diagnosis and Treatment.International journal of molecular sciences · 2024Review
- Oncoviral Infections and Small Extracellular Vesicles.Viruses · 2024Review
51 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Human immunodeficiency virus-associated neurological disorders (HANDs) affect the majority of AIDS patients and are a significant problem among HIV-1-infected individuals who live longer because of combined anti-retroviral therapies. HIV-1 utilizes a number of viral proteins and subsequent cytokine inductions to unleash its toxicity on neurons. Among HIV-1 viral proteins, Nef is a small protein expressed abundantly in astrocytes of HIV-1-infected brains and has been suggested to have a role in the pathogenesis of HAND. In order to explore its effect in the central nervous system, HIV-1 Nef was expressed in primary human fetal astrocytes (PHFAs) using an adenovirus. Our results revealed that HIV-1 Nef is released in extracellular vesicles (EVs) derived from PHFA cells expressing the protein. Interestingly, HIV-1 Nef release in EVs was enriched significantly when the cells were treated with autophagy activators perifosine, tomaxifen, MG-132, and autophagy inhibitors LY294002 and wortmannin suggesting a novel role of autophagy signaling in HIV-1 Nef release from astrocytes. Next, Nef-carrying EVs were purified from astrocyte cultures and neurotoxic effects on neurons were analyzed. We observed that HIV-1 Nef-containing EVs were readily taken up by neurons as demonstrated by immunocytochemistry and immunoblotting. Furthermore, treatment of neurons with Nef-carrying EVs induced oxidative stress as evidenced by a decrease in glutathione levels. To further investigate its neurotoxic effects, we expressed HIV-1 Nef in primary neurons by adenoviral transduction. Intracellular expression of HIV-1 Nef caused axonal and neurite degeneration of neurons. Furthermore, expression of HIV-1 Nef decreased the levels of phospho-tau while enhancing total tau in primary neurons. In addition, treatment of primary neurons with Nef-carrying EVs suppressed functional neuronal action potential assessed by multielectrode array studies. Collectively, these data suggested that HIV-1 Nef can be a formidable contributor to neurotoxicity along with other factors, which leads to HAND in HIV-1-infected AIDS patients.
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