HIV-1 Tat-Mediated Apoptosis in Human Blood-Retinal Barrier-Associated Cells

Che, Xin; He, Fanglin; Deng, Yuan; Xu, Shi-Qiong; Fan, Xianqun; Gu, Ping; Wang, Zhiliang

doi:10.1371/journal.pone.0095420

Cited by 14 publications

(13 citation statements)

References 41 publications

(47 reference statements)

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“…The apoptotic potential of HIV Tat has been recognized in a variety of cell types such as peripheral lymphocytes, central nervous system‐resident monocytes, astrocytes, dopaminergic and hippocampal neurons, and a range of endothelial cells—all of which presumably trigger both intrinsic and extrinsic apoptosis pathways . Consistent with these reports, we also demonstrated that Tat‐exposed Jurkat cells display a significant decrease in proliferation rate associated to an apoptosis‐like cellular profile.…”

Section: Discussionsupporting

confidence: 89%

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

Campestrini

Silveira

Pinto

2018

Cell Biochemistry & Function

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The HIV transactivator protein (Tat) is a multifunctional protein that plays a critical role in viral replication and contributes to several pathological symptoms of HIV‐1 infection, which has the loss of CD4+ T lymphocytes as one of its hallmark features. It has been shown that endoplasmic reticulum (ER) stress, including viral infections, is implicated in cellular dysfunction and cell death through activation of the unfolded protein response (UPR). Here, we demonstrate that the bystander stimulus of Tat on Jurkat cells resulted in time‐dependent overexpression of major UPR markers including ER chaperone BiP, ER stress sensors ATF6, PERK, and IRE1, as well as an increase in levels of downstream mediators eIF2α, ATF4, XBP‐1, and proapoptotic factors CHOP, GADD34, and BIM. This upregulation of UPR mediators was accompanied by decreased cell viability and increased apoptosis as evidenced by blue trypan dye exclusion and flow cytometry assays, respectively. Furthermore, we found that the Tat‐associated apoptosis of Jurkat cells led to the loss of mitochondrial membrane potential and caspase‐12 and ‐3 activation. Taken together, these results suggest that the exposure of HIV‐1 Tat leads to ER stress/UPR triggering which in turn contributes to apoptotic death in Jurkat cells. Significance of the study In the present work, we provide a substantial insight into the link between ER impairment and apoptotic death following a bystander HIV Tat stimulus, revealing an underlying ER‐mediated apoptotic mechanism which could explain the continuous depletion of uninfected CD4+ T lymphocytes observed in HIV‐related disease. Our findings reinforce the relevance of ER stress molecular responses in the course of HIV infection and may afford valuable information for the development of new therapeutic strategies to avoid CD4+ T lymphocyte loss and other disorders induced by circulant Tat.

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Section: Discussionsupporting

confidence: 89%

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

Campestrini

Silveira

Pinto

2018

Cell Biochemistry & Function

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“…In addition to pro-inflammatory mediators, they observed that retinal cells also demonstrated increased cell activation as evidenced by augmented expression of GFAP, which is due to the activation of Muller glial cells. Recent study by Che et al also emphasizes the role of HIV-1 Tat protein in the development of ocular complications during HIV infection [ 6 ]. HIV-1 Tat protein induced the apoptosis of human retinal microvascular endothelial cells and retinal pigment epithelium cells.…”

Section: Introductionmentioning

confidence: 99%

Immune Recovery Uveitis: Pathogenesis, Clinical Symptoms, and Treatment

Urban

Bakunowicz-Łazarczyk

Michalczuk

2014

Mediators of Inflammation

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IRU is the most common form of immune reconstitution inflammatory syndrome in HIV-infected patients with cytomegalovirus retinitis who are receiving highly active antiretroviral therapy (HAART). Among patients with CMV in the HAART era, immune recovery may be associated with a greater number of inflammatory complications, including macular edema and epiretinal membrane formation. Given the range of ocular manifestations of HIV, routine ocular examinations and screening for visual loss are recommended in patients with CD4 counts <50 cells/μL. With the increasing longevity of these patients due to the use of HAART, treatment of IRU may become an issue in the future. The aim of this paper is to review the current literature concerning immune recovery uveitis. The definition, epidemiology, pathophysiology, clinical findings, complications, diagnosis, and treatment are presented.

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“…HIV-1 Tat regulates host cell proliferation through various mechanisms including apoptosis 26 , translation 27 , 28 , and signal transduction 29 – 31 as well as mitosis 10 . Here, we provide new evidence that Tat may modulate cell proliferation by inhibiting mitosis through an interaction with RPS3.…”

Section: Discussionmentioning

confidence: 99%

Effect of HIV-1 Tat on the formation of the mitotic spindle by interaction with ribosomal protein S3

Kim

2018

Sci Rep

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Human immunodeficiency virus type 1 (HIV-1) Tat, an important regulator of viral transcription, interacts with diverse cellular proteins and promotes or inhibits cell proliferation. Here, we show that ribosomal protein S3 (RPS3) plays an important role in mitosis through an interaction with α-tubulin and that Tat binds to and inhibits the localization of RPS3 in the mitotic spindle during mitosis. RPS3 colocalized with α-tubulin around chromosomes in the mitotic spindle. Depletion of RPS3 promoted α-tubulin assembly, while overexpression of RPS3 impaired α-tubulin assembly. Depletion of RPS3 resulted in aberrant mitotic spindle formation, segregation failure, and defective abscission. Moreover, ectopic expression of RPS3 rescued the cell proliferation defect in RPS3-knockdown cells. HIV-1 Tat interacted with RPS3 through its basic domain and increased the level of RPS3 in the nucleus. Expression of Tat caused defects in mitotic spindle formation and chromosome assembly in mitosis. Moreover, the localization of RPS3 in the mitotic spindle was disrupted when HIV-1 Tat was expressed in HeLa and Jurkat cells. These results suggest that Tat inhibits cell proliferation via an interaction with RPS3 and thereby disrupts mitotic spindle formation during HIV-1 infection. These results might provide insight into the mechanism underlying lymphocyte pathogenesis during HIV-1 infection.

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HIV-1 Tat-Mediated Apoptosis in Human Blood-Retinal Barrier-Associated Cells

Cited by 14 publications

References 41 publications

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

Immune Recovery Uveitis: Pathogenesis, Clinical Symptoms, and Treatment

Effect of HIV-1 Tat on the formation of the mitotic spindle by interaction with ribosomal protein S3

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