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

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          Abstract

          HIV-1-associated ocular complications, such as microvasculopathies, can lead to the loss of vision in HIV-1-infected patients. Even in patients under highly active antiretroviral therapy, ocular lesions are unavoidable. Ocular complications have been demonstrated to be closely related to the breakdown of the blood-retinal-barrier (BRB); however, the underlying mechanism is not clear. The data from this study indicated that the HIV-1 Tat protein induced the apoptosis of human retinal microvascular endothelial cells (HRMECs) and retinal pigmen epithelium (RPE) cells, which compose the inner BRB and the outer BRB, respectively. In addition, this study found that the activation of N-methyl-D-aspartate receptors (NMDARs) was involved in the apoptosis of RPE cells, but it caused no changes in HRMECs. Furthermore, both cell types exhibited enhanced expression of Bak, Bax and Cytochrome c. The inhibition of Tat activity protected against the apoptosis induced by NMDAR activation and prevented the dysregulation of Bak, Bax and Cytochrome c, revealing an important role for the mitochondrial pathway in HIV-1 Tat-induced apoptosis. Together, these findings suggest a possible mechanism and may identify a potential therapeutic strategy for HIV-1-associated ocular complications.

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          Most cited references41

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          Mitochondria and apoptosis.

          D Green, J Reed (1998)
          A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.
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            Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

            The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.
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              Heteromeric NMDA receptors: molecular and functional distinction of subtypes.

              The N-methyl D-aspartate (NMDA) receptor subtype of glutamate-gated ion channels possesses high calcium permeability and unique voltage-dependent sensitivity to magnesium and is modulated by glycine. Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% identical in sequence. These are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor subunits, including the NMDA receptor subunit NMDAR1 (NR1). Upon expression in cultured cells, the new subunits yielded prominent, typical glutamate- and NMDA-activated currents only when they were in heteromeric configurations with NR1. NR1-NR2A and NR1-NR2C channels differed in gating behavior and magnesium sensitivity. Such heteromeric NMDA receptor subtypes may exist in neurons, since NR1 messenger RNA is synthesized throughout the mature rat brain, while NR2 messenger RNA show a differential distribution.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                16 April 2014
                : 9
                : 4
                : e95420
                Affiliations
                [1]Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
                Medical University of South Carolina, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: XC PG ZW. Performed the experiments: XC FH. Analyzed the data: XC YD SX. Wrote the paper: XC. Revised the manuscript: PG XF ZW.

                Article
                PONE-D-13-27678
                10.1371/journal.pone.0095420
                3989329
                24739951
                e5da04d2-5c6a-491a-8942-e7f7c732e790
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 July 2013
                : 27 March 2014
                Page count
                Pages: 9
                Funding
                This research was supported by the National Natural Science Foundations of China (81070757, 81070737). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Membrane Receptor Signaling
                Neurotransmitter Receptor Signaling
                Signaling Cascades
                Apoptotic Signaling Cascade
                Apoptotic Signaling
                Molecular Cell Biology
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Viral Pathogens
                Immunodeficiency Viruses
                HIV
                Medicine and health sciences
                Diagnostic medicine
                HIV clinical manifestations
                Infectious Diseases
                Viral Diseases
                Ophthalmology
                Retinal Disorders

                Uncategorized
                Uncategorized

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