scholarly journals HIV-Associated Neurotoxicity: The Interplay of Host and Viral Proteins

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Sushama Jadhav ◽  
Vijay Nema
Keyword(s):  
Chemokine Receptors ◽  
Viral Proteins ◽  
Neurocognitive Disorder ◽  
Asymptomatic Neurocognitive Impairment ◽  
Antiretroviral Agents ◽  
Aids Epidemic ◽  
Current Review ◽  
The Central Nervous System ◽  
The Brain ◽  
Hiv 1

HIV-1 can incite activation of chemokine receptors, inflammatory mediators, and glutamate receptor-mediated excitotoxicity. The mechanisms associated with such immune activation can disrupt neuronal and glial functions. HIV-associated neurocognitive disorder (HAND) is being observed since the beginning of the AIDS epidemic due to a change in the functional integrity of cells from the central nervous system (CNS). Even with the presence of antiretroviral therapy, there is a decline in the functioning of the brain especially movement skills, noticeable swings in mood, and routine performance activities. Under the umbrella of HAND, various symptomatic and asymptomatic conditions are categorized and are on a rise despite the use of newer antiretroviral agents. Due to the use of long-lasting antiretroviral agents, this deadly disease is becoming a manageable chronic condition with the occurrence of asymptomatic neurocognitive impairment (ANI), symptomatic mild neurocognitive disorder, or HIV-associated dementia. In-depth research in the pathogenesis of HIV has focused on various mechanisms involved in neuronal dysfunction and associated toxicities ultimately showcasing the involvement of various pathways. Increasing evidence-based studies have emphasized a need to focus and explore the specific pathways in inflammation-associated neurodegenerative disorders. In the current review, we have highlighted the association of various HIV proteins and neuronal cells with their involvement in various pathways responsible for the development of neurotoxicity.

scholarly journals Brain HIV-1 latently-infected reservoirs targeted by the suicide gene strategy

2020 ◽  
Author(s):  
Sepideh Saeb ◽  
Mehrdad Ravanshad ◽  
Mahmoud Reza Pourkarim ◽  
Fadoua Daouad ◽  
Kazem Baesi ◽  
...  
Keyword(s):  
Suicide Gene ◽  
Microglial Cells ◽  
Peripheral Tissues ◽  
Latently Infected ◽  
Shock And Kill ◽  
The Central Nervous System ◽  
Infected Cells ◽  
Set Up ◽  
The Brain ◽  
Hiv 1

Abstract Several strategies are currently investigated to reduce the pool of all HIV-1 reservoirs in infected patients in order to achieve functional cure. The most prominent HIV-1 cell reservoirs in the brain are microglial cells. Virus infection maybe lifelong. Infected microglial cells are believed to be the source of peripheral tissues reseeding and responsible for the emergence of drug resistance. Clearing infected cells from the brain is therefore crucial. However, many characteristics of microglial cells and the central nervous system prevent the eradication of brain reservoirs. Current trials, such as “shock and kill”, the “deep and lock” and the gene editing strategies do not respond to these difficulties. Therefore, new strategies have to be designed when considering brain reservoirs such as microglial cells. We set up an original gene suicide strategy using a latently infected microglial model. In this paper we provide proof of concept of this strategy. Our results demonstrate that this strategy enables the eradication of latently-infected microglial cells.

scholarly journals Chemokines and chemokine receptors in the brain: implication in neuroendocrine regulation

2007 ◽  
Vol 38 (3) ◽  
pp. 355-363 ◽  
Author(s):  
Céline Callewaere ◽  
Ghazal Banisadr ◽  
William Rostène ◽  
Stéphane Mélik Parsadaniantz
Keyword(s):  
Chemokine Receptors ◽  
Cell Types ◽  
Normal Brain ◽  
Ability To Act ◽  
The Central Nervous System ◽  
Neuronal Functions ◽  
The Brain ◽  
Neuroendocrine Functions

Chemokines are small secreted proteins that chemoattract and activate immune and non-immune cells both in vivo and in vitro. In addition to their well-established role in the immune system, several recent reports have suggested that chemokines and their receptors may also play a role in the central nervous system (CNS). The best known central action is their ability to act as immunoinflammatory mediators. Indeed, these proteins regulate leukocyte infiltration in the brain during inflammatory and infectious diseases. However, we and others recently demonstrated that they are expressed not only in neuroinflammatory conditions, but also constitutively by different cell types including neurons in the normal brain, suggesting that they may act as modulators of neuronal functions. The goal of this review is to highlight the role of chemokines in the control of neuroendocrine functions. First, we will focus on the expression of chemokines and their receptors in the CNS, with the main spotlight on the neuronal expression in the hypothalamo–pituitary system. Secondly, we will discuss the role – we can now suspect – of chemokines and their receptors in the regulation of neuroendocrine functions. In conclusion, we propose that chemokines can be added to the well-described neuroendocrine regulatory mechanisms, providing an additional fine modulatory tuning system in physiological conditions.

scholarly journals MCP-1 and CCR2 Contribute to Non-Lymphocyte-Mediated Brain Disease Induced by Fr98 Polytropic Retrovirus Infection in Mice: Role for Astrocytes in Retroviral Neuropathogenesis

2004 ◽  
Vol 78 (12) ◽  
pp. 6449-6458 ◽  
Author(s):  
Karin E. Peterson ◽  
John S. Errett ◽  
Tao Wei ◽  
Derek E. Dimcheff ◽  
Richard Ransohoff ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Neurological Disease ◽  
Chemokine Receptors ◽  
Disease Process ◽  
Chemotactic Protein ◽  
The Central Nervous System ◽  
Brain Antibody ◽  
The Brain

ABSTRACT Virus infection of the central nervous system (CNS) often results in chemokine upregulation. Although often associated with lymphocyte recruitment, increased chemokine expression is also associated with non-lymphocyte-mediated CNS disease. In these instances, the effect of chemokine upregulation on neurological disease is unclear. In vitro, several chemokines including monocyte chemotactic protein 1 (MCP-1) protect neurons from apoptosis. Therefore, in vivo, chemokine upregulation may be a protective host response to CNS damage. Alternatively, chemokines may contribute to pathogenesis by stimulating intrinsic brain cells or recruiting macrophages to the brain. To investigate these possibilities, we studied a neurovirulent retrovirus, Fr98, that induces severe non-lymphocyte-mediated neurological disease and causes the upregulation of several chemokines that bind to chemokine receptors CCR2 and CCR5. Knockout mice deficient in CCR2 had reduced susceptibility to Fr98 pathogenesis, with significantly fewer mice developing clinical disease than did wild-type controls. In contrast, no reduction in Fr98-induced disease was observed in CCR5 knockout mice. Thus, signaling through CCR2, but not CCR5, plays an important role in Fr98-mediated pathogenesis. Three ligands for CCR2 (MCP-1, MCP-3, and MCP-5) were upregulated during Fr98 infection of the brain. Antibody-blocking experiments demonstrated that MCP-1 was important for retrovirus-induced neurological disease. In situ hybridization analysis revealed that MCP-1 was expressed by glial fibrillary acidic protein-positive astrocytes. Thus, astrocytes, previously not thought to play an effector role in the disease process were found to contribute to pathogenesis through the production of MCP-1. This study also demonstrates that chemokines can mediate pathogenesis in the CNS in the absence of lymphocytic infiltrate and gives credence to the hypothesis that chemokine upregulation is a mechanism by which retroviruses such as human immunodeficiency virus induce neurological damage.

scholarly journals Microglia Express CCR5, CXCR4, and CCR3, but of These, CCR5 Is the Principal Coreceptor for Human Immunodeficiency Virus Type 1 Dementia Isolates

1999 ◽  
Vol 73 (1) ◽  
pp. 205-213 ◽  
Author(s):  
Andrew V. Albright ◽  
Joseph T. C. Shieh ◽  
Takayuki Itoh ◽  
Benhur Lee ◽  
David Pleasure ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Chemokine Receptors ◽  
Calcium Flux ◽  
Human Adult ◽  
Immunodeficiency Virus ◽  
The Central Nervous System ◽  
Hiv Entry ◽  
G Protein Coupled ◽  
Hiv 1

ABSTRACT Microglia are the main human immunodeficiency virus (HIV) reservoir in the central nervous system and most likely play a major role in the development of HIV dementia (HIVD). To characterize human adult microglial chemokine receptors, we analyzed the expression and calcium signaling of CCR5, CCR3, and CXCR4 and their roles in HIV entry. Microglia expressed higher levels of CCR5 than of either CCR3 or CXCR4. Of these three chemokine receptors, only CCR5 and CXCR4 were able to transduce a signal in microglia in response to their respective ligands, MIP-1β and SDF-1α, as recorded by single-cell calcium flux experiments. We also found that CCR5 is the predominant coreceptor used for infection of human adult microglia by the HIV type 1 dementia isolates HIV-1DS-br, HIV-1RC-br, and HIV-1YU-2, since the anti-CCR5 antibody 2D7 was able to dramatically inhibit microglial infection by both wild-type and single-round luciferase pseudotype reporter viruses. Anti-CCR3 (7B11) and anti-CXCR4 (12G5) antibodies had little or no effect on infection. Last, we found that virus pseudotyped with the DS-br and RC-br envelopes can infect cells transfected with CD4 in conjunction with the G-protein-coupled receptors APJ, CCR8, and GPR15, which have been previously implicated in HIV entry.

scholarly journals The Cytomegalovirus-Encoded Chemokine Receptor US28 Can Enhance Cell-Cell Fusion Mediated by Different Viral Proteins

1998 ◽  
Vol 72 (8) ◽  
pp. 6389-6397 ◽  
Author(s):  
Olivier Pleskoff ◽  
Carole Tréboute ◽  
Marc Alizon
Keyword(s):  
Cell Fusion ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Viral Proteins ◽  
Specific Factor ◽  
Target Cells ◽  
A Cell ◽  
Vesicular Stomatitis ◽  
Positive Effect ◽  
Hiv 1

ABSTRACT The human cytomegalovirus (CMV) US28 gene encodes a functional CC chemokine receptor. However, this activity was observed in cells transfected to express US28 and might not correspond to the actual role of the protein in the CMV life cycle. Expression of US28 allows human immunodeficiency virus type 1 (HIV-1) entry into certain CD4+ cells and their fusion with cells expressing HIV-1 envelope (Env) proteins. Such properties were initially reported for the cellular chemokine receptors CCR5 and CXCR4, which behave as CD4-associated HIV-1 coreceptors. We found that coexpression of US28 and either CXCR4 or CCR5 in CD4+ cells resulted in enhanced synctium formation with HIV-1 Env+ cells. This positive effect of US28 on cell fusion seems to be distinct from its HIV-1 coreceptor activity. Indeed, enhancement of cell fusion was also observed when US28 was expressed on the HIV-1 Env+ cells instead of an CD4+ target cells. Furthermore, US28 could enhance cell fusion mediated by other viral proteins, in particular, the G protein of vesicular stomatitis virus (VSV-G). The HIV-1 coreceptor and fusion-enhancing activities could be affected by mutations in different domains of US28. The fusion-enhancing activity of US28 seems to be cell type dependent. Indeed, cells coexpressing VSV-G and US28 fused more efficiently with human, simian, or feline target cells, while US28 had no apparent effect on fusion with the three mouse or rat cell lines tested. The positive effect of US28 on cell fusion might therefore require its interaction with a cell-specific factor. We discuss a possible role for US28 in the fusion of the CMV envelope with target cells and CMV entry.

Chemokine receptors in HIV-1 infection of the central nervous system

1998 ◽  
Vol 10 (3) ◽  
pp. 203-213 ◽  
Author(s):  
Dana Gabuzda ◽  
Jianglin He ◽  
Asa Ohagen ◽  
Anne-Valérie Vallat
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Chemokine Receptors ◽  
The Central Nervous System ◽  
Hiv 1

scholarly journals COVID-19 Neuropathology: Evidence for SARS-CoV-2 invasion of Human Brainstem Nuclei

2021 ◽  
Author(s):  
Aron Emmi ◽  
Stefania Rizzo ◽  
Luisa Barzon ◽  
Elisa Carturan ◽  
Alessandro Sinigaglia ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Viral Proteins ◽  
Nucleus Ambiguus ◽  
Rt Pcr ◽  
Reactive Microglia ◽  
Direct Invasion ◽  
Immune Mediated ◽  
The Central Nervous System ◽  
Study Support ◽  
The Brain

Abstract Neurological manifestations are common in COVID-19, the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Despite some reports of detection of SARS-CoV-2 in the brain and cerebrospinal fluid of patients with COVID-19, it is still unclear whether the virus can infect the central nervous system (CNS), and which neuropathological alterations can be ascribed to viral tropism rather than immune-mediated mechanisms. Available autopsy reports are often conflictual, reporting a heterogeneous spectrum of neuropathological alterations, while viral proteins and RNA were detected only in sparse cells within the brainstem; furthermore, there appears to be no consistent correlation between viral invasion and neuropathological alterations to date. Here, we assess the neuropathological changes occurring in 24 patients who died following a diagnosis of SARS-CoV-2 infection in Italy during the COVID-19 pandemic (from March 2020 to May 2021) and 10 age-matched controls with comparable medical conditions. Aside from a wide spectrum of neuropathological alterations, including astrogliosis, sparse lympho-monocytic infiltrations and several instances of small vessel thromboses, we identified 5 COVID-19 subjects presenting SARS-CoV-2-immunoreactive neurons within the boundaries of the solitary tract nucleus, nucleus ambiguus and substantia nigra in the brainstem. In these subjects, viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation targeting mainly the medulla oblongata and the mesencephalon, and was significantly higher when compared to controls. However, SARS-CoV-2 direct invasion did not appear to correlate with the severity of neuropathological changes. The results of this study support the neuroinvasive potential of SARS-CoV-2 by demonstrating the presence of viral proteins and genome sequences within the human brainstem, but further investigation is required to identify the link between invasion and consequent neuropathological alterations in humans.

scholarly journals Tetraspanins as Potential Modulators of Glutamatergic Synaptic Function

2022 ◽  
Vol 14 ◽  
Author(s):  
Amina Becic ◽  
Jennifer Leifeld ◽  
Javeria Shaukat ◽  
Michael Hollmann
Keyword(s):  
Protein Trafficking ◽  
Current Knowledge ◽  
Cell Types ◽  
Synaptic Function ◽  
Glutamatergic Synaptic Transmission ◽  
Specific Proteins ◽  
The Central Nervous System ◽  
Almost All ◽  
The Brain ◽  
Hiv 1

Tetraspanins (Tspans) comprise a membrane protein family structurally defined by four transmembrane domains and intracellular N and C termini that is found in almost all cell types and tissues of eukaryotes. Moreover, they are involved in a bewildering multitude of diverse biological processes such as cell adhesion, motility, protein trafficking, signaling, proliferation, and regulation of the immune system. Beside their physiological roles, they are linked to many pathophysiological phenomena, including tumor progression regulation, HIV-1 replication, diabetes, and hepatitis. Tetraspanins are involved in the formation of extensive protein networks, through interactions not only with themselves but also with numerous other specific proteins, including regulatory proteins in the central nervous system (CNS). Interestingly, recent studies showed that Tspan7 impacts dendritic spine formation, glutamatergic synaptic transmission and plasticity, and that Tspan6 is correlated with epilepsy and intellectual disability (formerly known as mental retardation), highlighting the importance of particular tetraspanins and their involvement in critical processes in the CNS. In this review, we summarize the current knowledge of tetraspanin functions in the brain, with a particular focus on their impact on glutamatergic neurotransmission. In addition, we compare available resolved structures of tetraspanin family members to those of auxiliary proteins of glutamate receptors that are known for their modulatory effects.

scholarly journals HIV-1 Tat Protein-Induced Alterations of ZO-1 Expression are Mediated by Redox-Regulated ERK1/2 Activation

2005 ◽  
Vol 25 (10) ◽  
pp. 1325-1335 ◽  
Author(s):  
Hong Pu ◽  
Jing Tian ◽  
Ibolya E Andras ◽  
Kentaro Hayashi ◽  
Govinder Flora ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Inflammatory Cells ◽  
Mrna Levels ◽  
Tat Protein ◽  
Extracellular Signal ◽  
Junction Protein ◽  
The Central Nervous System ◽  
The Right ◽  
The Brain ◽  
Hiv 1

HIV-1 Tat protein plays an important role in inducing monocyte infiltration into the brain and may alter the structure and functions of the blood—brain barrier (BBB). The BBB serves as a frontline defense system, protecting the central nervous system from infected monocytes entering the brain. Therefore, the aim of the present study was to examine the mechanisms of Tat effect on the integrity of the BBB in the mouse brain. Tat was injected into the right hippocampi of C57BL/6 mice and expression of tight junction protein zonula occludens-1 (ZO-1) was determined in control and treated mice. Tat administration resulted in decreased mRNA levels of ZO-1 and marked disruption of ZO-1 continuity. These changes were associated with accumulation of inflammatory cells in brain tissue of Tat-treated mice. Further experiments indicated that Tat-mediated alterations of redox-related signaling may be responsible for decreased ZO-1 expression. Specifically, injections with Tat resulted in activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and pretreatment with U0126, a specific inhibitor of ERK kinase, effectively ameliorated the Tat-induced diminished ZO-1 levels. In addition, administration of N-acetylcysteine (NAC), a precursor of glutathione and a potent antioxidant, attenuated both Tat-induced ERK1/2 activation and alterations in ZO-1 expression. These results indicate that Tat-induced oxidative stress can play an important role in affecting the integrity of the BBB through the ERK1/2 pathway.

Sign in / Sign up

Export Citation Format

Share Document