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

Abstract

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.

Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

“…It was observed that Tat remained near to the mitochondria [ 57 , 58 ], suggesting cellular distribution is related to organelle alterations. Accordingly, other findings revealed that Tat-exposed cells present mtDNA damage [ 20 , 59 ] and alteration in its methylation patterns [ 60 ], mitochondrial membrane potential reduction [ 23 ] changes in size and morphology of the organelle, fusion-fission triggering [ 24 ], increased mitochondrial ROS [ 61 , 62 ], mitophagy disruption [ 17 , 57 ], mitochondrial functions dysregulation [ 17 , 61 ] calcium homeostasis disturbance [ 61 , 63 , 64 ], and apoptosis activation [ 23 , 58 , 61 , 65 , 66 ].…”

“…The reported data shows that Tat-exposed cells undergo extrinsic [ 65 ] and intrinsic apoptosis pathways [ 23 ]. In the first one, the signaling process starts in the cell membrane and is triggered by stimulation of death receptors, followed by activation of caspases to initiate cell death.…”

“…In animal models and cell lines, it has been observed that transactivator of transcription (Tat) induces alterations in CNS [ 17 , 18 , 19 , 20 , 21 ]. A hallmark in Tat-induced neurodegeneration is endoplasmic reticulum (ER) stress [ 22 , 23 ] and mitochondrial dysfunction, which are characterized by disruptions in mitophagy [ 18 ], mtDNA [ 20 ], fusion and fission [ 24 ], and energy metabolism [ 25 , 26 ]. SIRTs, NAD+-dependent deacetylases, are involved in molecular mechanisms of these mitochondrial processes [ 27 , 28 ].…”

Cal‘MAM’ity at the Endoplasmic Reticulum-Mitochondrial Interface: A Potential Therapeutic Target for Neurodegeneration and Human Immunodeficiency Virus-Associated Neurocognitive Disorders

“…Moreover, studies from our lab demonstrate induction of the three UPR pathways in primary human astrocytes in response to HAND-relevant stimuli (whole HIV-1, inflammation, and ART drugs), which associate with mitochondrial depolarization ( Nooka and Ghorpade, 2017 ). HIV-1 Tat-induced ER stress in a CD4+ T cell line ( Campestrini et al, 2018 ) neurons ( Norman et al, 2008 ) and human brain microvascular endothelial cells (HBMEC) ( Ma et al, 2016 ) are also accompanied by changes in mitochondrial function and apoptotic signaling supporting cooperation of the ER and mitochondria during HIV/HAND pathology. Indeed, inhibition of ER stress reversed HIV-1-induced mitochondrial dysfunction and increased cell viability in HBMEC ( Ma et al, 2016 ).…”

Recognition of Apoptotic Cells by Viruses and Cytolytic Lymphocytes: Target Selection in the Fog of War

“…This would prevent dead-end entry into doomed hosts, which are incapable of supporting productive infection. For example, HIV and SIV replicate primarily in a setting of increased uninfected CD4 + lymphocyte proliferation and turnover, marked by activation-induced cell death due to Fas and other contact-triggered suicide initiators, including uninfected cell contact with infected cells (13,30,51,57,60,64,87). Most leukocytes die within 12 h of initiating programmed cell death in vitro, and cell machinery required for viral integration, replication, assembly, and budding is compromised much sooner (23).…”