HIV-Tat regulates macrophage gene expression in the context of neuroAIDS

Carvallo, Loreto; Lopez, Lillie; Fajardo, J. Eduardo; Jaureguiberry‐Bravo, Matias; Fiser, András; Berman, Joan W.

doi:10.1371/journal.pone.0179882

Cited by 24 publications

(31 citation statements)

References 125 publications

(121 reference statements)

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“…The Sirt1-mediated control of those inflammatory targets was examined in non-infectious models, using both THP1 myeloid cell lines stimulated with CpG Oligo-deoxynucleotides (CpG ODN), a TLR9 agonist with pro-inflammatory effects, and primary human monocytes stimulated with the HIV Tat peptide, which has a reported effect on inflammatory gene transcription(Carvallo et al 2017). These in vitro models verified the consistency of the ability of Sirt-1 to modulate the transcriptional expression of inflammatory markers prioritized in this study.…”

Section: Resultsmentioning

confidence: 99%

Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain

Bortell

Basova

Najera

et al. 2017

J Neuroimmune Pharmacol

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Microglia and macrophages are the main non-neuronal subsets of myeloid origin in the brain, and are critical regulators in neurodegenerative disorders, where inflammation is a key factor. Since HIV infection results in neurological perturbations that are similar to those in aging, we examined microglial and infiltrating myeloid subsets in the search for changes that might resemble the ones in aging. For that, we used the SIV infection in rhesus macaques to model neuroAIDS. We found that Sirt-1, a molecule that impacts survival and health in many models, was decreased in cell preparations containing a majority of microglia and myeloid cells from the brain of infected macaques. The role of Sirt-1 in neuroAIDS is unknown. We hypothesized that Sirt-1 silencing functions are affected by SIV. Mapping of Sirt-1 binding patterns to chromatin revealed that the number of Sirt-1-bound genes was 29.6% increased in myeloid cells from infected animals with mild or no detectable neuropathology, but 51% was decreased in severe neuropathology, compared to controls. Importantly, Sirt-1-bound genes in controls largely participate in neuroinflammation. Promoters of type I IFN pathway genes IRF7, IRF1, IFIT1, and AIF1, showed Sirt-1 binding in controls, which was consistently lost after infection, together with higher transcription. Loss of Sirt-1 binding was also found in brains from old uninfected animals, suggesting a common regulation. The role of Sirt-1 in regulating these inflammatory markers was confirmed in two different in vitro models, where Sirt-1 blockage modulated IRF7, IRF1 and AIF1 levels both in human macrophage cell lines and in human blood-derived monocytes from various normal donors, stimulated with a TLR9 agonist. Our data suggests that Sirt-1-inflammatory gene silencing is disturbed by SIV infection, resembling aging in brains. These findings may impact our knowledge on the contribution of myeloid subsets to the neurological consequences of HIV infection, aggravated and overlapping with the aging process.

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Section: Resultsmentioning

confidence: 99%

Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain

Bortell

Basova

Najera

et al. 2017

J Neuroimmune Pharmacol

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“…The underlying pathogenesis of acquired immunodeficiency syndrome (AIDS) has been attributed to a progressive depletion of CD4 + T lymphocytes through several different mechanisms such as apoptosis, cellular syncytia, plasma membrane disruption by viral budding, CD8 + T lymphocyte response, or cytotoxicity by released viral proteins to extracellular milieu . Among these viral proteins, the HIV trans‐activator (Tat), a 14 to 16‐kDa peptide synthesized and secreted at both early and late stages of viral replication, is described as a pivotal factor during the course of HIV infection since it enhances transcription through binding to the transactivator response element (TAR) region at the 5′ end of newly formed viral RNA transcripts . Following TAR binding, Tat is able to recruit the cellular apparatus that promotes chromatin‐remodelling and phosphorylation of RNA polymerase II.…”

Section: Introductionmentioning

confidence: 99%

“…Following TAR binding, Tat is able to recruit the cellular apparatus that promotes chromatin‐remodelling and phosphorylation of RNA polymerase II. This enhances the processivity of the elongating polymerase and stimulates the assembly of new transcription complexes . Beyond its role on viral transcription, Tat has been proposed to modulate the expression of several other genes, to interact with a large number of host cell proteins, and to inhibit several cellular metabolic pathways .…”

Section: Introductionmentioning

confidence: 99%

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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“…The frequency of HIV‐1‐associated dementia has significantly declined with the advent of cART therapy; however, milder forms of neurocognitive impairment remain prevalent . Several reports suggest that low‐level HIV‐1 replication in microglia and secretion of viral proteins (eg, Tat, Vpr) can result in chronic inflammatory responses in the brain . Although significant efforts have been invested to identify an effective compound for the treatment of HAND, currently, there is no treatment that has consistently demonstrated improvements in cognition clinically.…”

Section: Discussionmentioning

confidence: 99%

Selective peroxisome proliferator‐activated receptor‐gamma modulator, INT131 exhibits anti‐inflammatory effects in an EcoHIV mouse model

et al. 2019

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Despite the use of antiretroviral therapy for the treatment of HIV‐1 infection, cognitive impairments, that is, HIV‐1‐associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, associated brain inflammation or in certain instances, antiretroviral neurotoxicity. Cellular targets in the brain include microglia which in response to infection release inflammatory markers and viral proteins. Evidence suggests that PPARγ agonists exert anti‐inflammatory properties in neurological disorders. However, these agonists namely, thiazolidinediones have limited use in the clinic due to reported adverse side effects. INT131 is a novel non‐thiazolidinedione compound that belongs to a new class of drugs known as selective PPARγ modulators. INT131 is considered to have a safer profile; however, its neuroprotective role in vivo is not known.The goal of this study was to examine the effect of INT131 in the context of EcoHIV‐induced inflammation in vitro, in primary cultures of mouse glial cells and in vivo, in a mouse model of EcoHIV‐associated brain inflammation, as well as characterize its pharmacokinetic properties and brain penetration. In primary cultures of glial cells and in the in vivo mouse model, EcoHIV exposure resulted in a significant elevation of inflammatory markers such as TNFα, IL‐1β, CCL3, and C3 which were attenuated with INT131 treatment. Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV‐1‐associated brain inflammation.

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HIV-Tat regulates macrophage gene expression in the context of neuroAIDS

Cited by 24 publications

References 125 publications

Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain

Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain

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

Selective peroxisome proliferator‐activated receptor‐gamma modulator, INT131 exhibits anti‐inflammatory effects in an EcoHIV mouse model

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