Extracellular HIV-1 Tat Mediates Increased Glutamate in the CNS Leading to Onset of Senescence and Progression of HAND

Marino, Jamie; Wigdahl, Brian; Nonnemacher, Michael R.

doi:10.3389/fnagi.2020.00168

Cited by 28 publications

(10 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dangerously, the process may occur on the background of successful ART, in the absence of active HIV-1 replication and viral production. Considering that approximately 2/3 of all Tat expressed by infected T cells is secreted [ 170 ], the activities of Tat described above make a considerable contribution into HIV-1 associated pathologies [ 171 , 172 ].…”

Section: Oncogenic Hiv-1 Proteins Inducing Oxidative Stress Are Fomentioning

confidence: 99%

Oncogenic Effects of HIV-1 Proteins, Mechanisms Behind

Isaguliants

Bayurova

Avdoshina

et al. 2021

Cancers

View full text Add to dashboard Cite

People living with human immunodeficiency virus (HIV-1) are at increased risk of developing cancer, such as Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), cervical cancer, and other cancers associated with chronic viral infections. Traditionally, this is linked to HIV-1-induced immune suppression with depletion of CD4+ T-helper cells, exhaustion of lymphopoiesis and lymphocyte dysfunction. However, the long-term successful implementation of antiretroviral therapy (ART) with an early start did not preclude the oncological complications, implying that HIV-1 and its antigens are directly involved in carcinogenesis and may exert their effects on the background of restored immune system even when present at extremely low levels. Experimental data indicate that HIV-1 virions and single viral antigens can enter a wide variety of cells, including epithelial. This review is focused on the effects of five viral proteins: envelope protein gp120, accessory protein negative factor Nef, matrix protein p17, transactivator of transcription Tat and reverse transcriptase RT. Gp120, Nef, p17, Tat, and RT cause oxidative stress, can be released from HIV-1-infected cells and are oncogenic. All five are in a position to affect “innocent” bystander cells, specifically, to cause the propagation of (pre)existing malignant and malignant transformation of normal epithelial cells, giving grounds to the direct carcinogenic effects of HIV-1.

show abstract

Section: Oncogenic Hiv-1 Proteins Inducing Oxidative Stress Are Fomentioning

confidence: 99%

Oncogenic Effects of HIV-1 Proteins, Mechanisms Behind

Isaguliants

Bayurova

Avdoshina

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Glutamate excitotoxicity due to impaired glutamate uptake by astrocytes is one of the major contributors of astrocyte-mediated neuronal death in HIV-1 induced neurodegeneration ( Marino et al, 2020b ). This lowered uptake of glutamate by astrocytes is owed to the disruption of the glutamate transporters, EAAT1 and EAAT2 on astrocytes.…”

Section: Resultsmentioning

confidence: 99%

Role of EphrinA3 in HIV-1 Neuropathogenesis

et al. 2021

View full text Add to dashboard Cite

Glial cells perform important supporting functions for neurons through a dynamic crosstalk. Neuron–glia communication is the major phenomenon to sustain homeostatic functioning of the brain. Several interactive pathways between neurons and astrocytes are critical for the optimal functioning of neurons, and one such pathway is the ephrinA3–ephA4 signaling. The role of this pathway is essential in maintaining the levels of extracellular glutamate by regulating the excitatory amino acid transporters, EAAT1 and EAAT2 on astrocytes. Human immunodeficiency virus-1 (HIV-1) and its proteins cause glutamate excitotoxicity due to excess glutamate levels at sites of high synaptic activity. This study unravels the effects of HIV-1 transactivator of transcription (Tat) from clade B on ephrinA3 and its role in regulating glutamate levels in astrocyte–neuron co-cultures of human origin. It was observed that the expression of ephrinA3 increases in the presence of HIV-1 Tat B, while the expression of EAAT1 and EAAT2 was attenuated. This led to reduced glutamate uptake and therefore high neuronal death due to glutamate excitotoxicity. Knockdown of ephrinA3 using small interfering RNA, in the presence of HIV-1 Tat B reversed the neurotoxic effects of HIV-1 Tat B via increased expression of glutamate transporters that reduced the levels of extracellular glutamate. The in vitro findings were validated in autopsy brain sections from acquired immunodeficiency syndrome patients and we found ephrinA3 to be upregulated in the case of HIV-1-infected patients. This study offers valuable insights into astrocyte-mediated neuronal damage in HIV-1 neuropathogenesis.

show abstract

“…The underlying pathogenesis of HAND remains only partially understood, but it has been highlighted that HIV‐1 trans‐activator (Tat) protein, an early viral product continually secreted from infected cells, is a key component in HIV‐1‐mediated brain damage 3,4 . Extracellular Tat is biologically active and can directly depolarize neurons by interacting with a variety of surface receptors and thus potentiating glutamate‐induced excitotoxicity and death 5‐8 . Additionally, Tat induces neurotoxicity through indirect mechanisms via bystander effects on glial cells by modulating the synthesis of potentially neuroinflammatory mediators 9,10 .…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Extracellular Tat is biologically active and can directly depolarize neurons by interacting with a variety of surface receptors and thus potentiating glutamate-induced excitotoxicity and death. [5][6][7][8] Additionally, Tat induces neurotoxicity through indirect mechanisms via bystander effects on glial cells by modulating the synthesis of potentially neuroinflammatory mediators. 9,10 HIV-1 Tat-derived activation of microglia, the brain-resident immune cells, triggers a proinflammatory cell phenotype (M1) characterized by overexpression of cytokines and chemokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), as well as reactive oxygen species and nitric oxide (NO).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of UPR sensor PERK attenuates HIV Tat‐induced inflammatory M1 phenotype in microglial cells

Silveira

Américo

Flores

et al. 2022

Cell Biochemistry & Function

View full text Add to dashboard Cite

HIV‐1‐associated neurocognitive disorders (HAND) are a major concern in HIV‐infected individuals despite the currently available antiretroviral therapy regime. Impaired M1 pro‐inflammatory microglial activation is considered one of the hallmark features of HAND neuropathogenesis, and it has been suggested that circulant HIV‐1 transactivator protein (Tat) can play a critical role in this process. At the same time, endoplasmatic reticulum (ER) stress has also been implicated in neurodegenerative conditions resulting from the accumulation of misfolded proteins and subsequent unfolded protein response (UPR) deflagration. Here, we demonstrate that pharmacological inhibition of UPR‐related protein kinase R‐like endoplasmic reticulum kinase (PERK) can attenuate HIV‐1 Tat‐induced M1 inflammatory state in microglia in vitro. Our initial experiments demonstrate that the bystander stimulus of recombinant Tat on BV‐2 microglial cells result in the coupled overexpression of central UPR markers and pro‐inflammatory mediators such as iNOS, surface CD16/32 and secreted tumour necrosis factor‐α (TNF‐α), IL‐6, monocyte chemoattractant protein (MCP)‐1 and NO. We show that blocking PERK‐eIF2‐α‐ATF4 signalling using the PERK inhibitor GSK2606414 leads to reduced inflammatory response in M1‐like BV‐2 cells activated by recombinant Tat. Taken together, these findings suggest that PERK targeting may provide a therapeutic intervention to mitigate against lasting neuroinflammation and neuronal loss in of HAND.

show abstract

Extracellular HIV-1 Tat Mediates Increased Glutamate in the CNS Leading to Onset of Senescence and Progression of HAND

Cited by 28 publications

References 69 publications

Oncogenic Effects of HIV-1 Proteins, Mechanisms Behind

Oncogenic Effects of HIV-1 Proteins, Mechanisms Behind

Role of EphrinA3 in HIV-1 Neuropathogenesis

Pharmacological inhibition of UPR sensor PERK attenuates HIV Tat‐induced inflammatory M1 phenotype in microglial cells

Contact Info

Product

Resources

About