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      HIV-1 Transactivator Protein Induces ZO-1 and Neprilysin Dysfunction in Brain Endothelial Cells via the Ras Signaling Pathway

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          Abstract

          Amyloid beta (A β) deposition is increased in human immunodeficiency virus-1- (HIV-1-) infected brain, but the mechanisms are not fully understood. The aim of the present study was to evaluate the role of Ras signaling in HIV-1 transactivator protein- (Tat-) induced A β accumulation in human cerebral microvascular endothelial cells (HBEC-5i). Cell viability assay showed that 1  μg/mL Tat and 20  μmol/L of the Ras inhibitor farnesylthiosalicylic acid (FTS) had no significant effect on HBEC-5i cell viability after 24 h exposure. Exposure to Tat decreased protein and mRNA levels of zonula occludens- (ZO-) 1 and A β-degrading enzyme neprilysin (NEP) in HBEC-5i cells as determined by western blotting and quantitative real-time polymerase chain reaction. Exposure to Tat also increased transendothelial transfer of A β and intracellular reactive oxygen species (ROS) levels; however, these effects were attenuated by FTS. Collectively, these results suggest that the Ras signaling pathway is involved in HIV-1 Tat-induced changes in ZO-1 and NEP, as well as A β deposition in HBEC-5i cells. FTS partially protects blood-brain barrier (BBB) integrity and inhibits A β accumulation.

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          Most cited references42

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          Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort.

          Antiretroviral therapy has improved survival for HIV-1-infected individuals. The neuroepidemiologic implications of HIV-1 in an aging population are not well known, particularly the prevalence of HIV-associated dementia (HAD). The authors report a baseline cross-sectional analysis of 202 HIV-1-seropositive individuals enrolled into one of two groups of the Hawaii Aging with HIV Cohort: older (50 or more years old, n = 106) and younger (20 to 39 years old, n = 96). Neuropsychological, neurologic, medical, and laboratory data were obtained at enrollment. Participant cognitive status was classified (research case definitions) using American Academy of Neurology (1991) criteria in a consensus conference of physicians and neuropsychologists. HAD was more frequent in older (25.2%) compared to younger (13.7%) individuals (p = 0.041) corresponding to an OR of 2.13 (95% CI: 1.02 to 4.44) for the older compared to the younger group. After adjusting for education, race, substance dependence, antiretroviral medication status, viral load, CD4 lymphocyte count, and Beck Depression Inventory score, the odds of having HAD among individuals in the older group was 3.26 (1.32 to 8.07) times that of the younger group. Older age is associated with increased HAD in this HIV-1 cohort. Underlying mechanisms are unclear but do not appear related to duration of HIV-1 infection.
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            Breaking down the barrier: the effects of HIV-1 on the blood-brain barrier.

            Human immunodeficiency virus type 1 (HIV-1) primarily infects CD4(+) T cells and cells of the monocyte-macrophage lineage, resulting in immunodeficiency in an infected patient. Along with this immune deficiency, HIV-1 has been linked to a number of neurological symptoms in the absence of opportunistic infections or other co-morbidities, suggesting that HIV-1 is able to cross the blood-brain barrier (BBB), enter the central nervous system (CNS), and cause neurocognitive impairment. HIV-1-infected monocyte-macrophages traverse the BBB and enter the CNS throughout the course of HIV-1 disease. Once in the brain, both free virus and virus-infected cells are able to infect neighboring resident microglia and astrocytes and possibly other cell types. HIV-1-infected cells in both the periphery and the CNS give rise to elevated levels of viral proteins, including gp120, Tat, and Nef, and of host inflammatory mediators such as cytokines and chemokines. It has been shown that the viral proteins may act alone or in concert with host cytokines and chemokines, affecting the integrity of the BBB. The pathological end point of these interactions may facilitate a positive feedback loop resulting in increased penetration of HIV into the CNS. It is proposed in this review that the dysregulation of the BBB during and after neuroinvasion is a critical component of the neuropathogenic process and that dysregulation of this protective barrier is caused by a combination of viral and host factors including secreted viral proteins, components of the inflammatory process, the aging process, therapeutics, and drug or alcohol abuse. Copyright © 2011 Elsevier B.V. All rights reserved.
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              Increased accumulation of intraneuronal amyloid beta in HIV-infected patients.

              In recent years, human immunodeficiency virus (HIV)-infected patients under highly active anti-retroviral therapy (HAART) regimens have shown a markedly improved general clinical status; however, the prevalence of mild cognitive disorders has increased. We propose that increased longevity with HIV-mediated chronic inflammation combined with the secondary effects of HAART may increase the risk of early brain aging as shown by intraneuronal accumulation of abnormal protein aggregates like amyloid beta (Abeta), which might participate in worsening the neurodegenerative process and cognitive impairment in older patients with HIV. For this purpose, levels and distribution of Abeta immunoreactivity were analyzed in the frontal cortex of 43 patients with HIV (ages 38-60) and HIV- age-matched controls. Subcellular localization of the Abeta-immunoreactive material was analyzed by double labeling and confocal microscopy and by immunono-electron microscopy (EM). Compared to HIV- cases, in HIV+ cases, there was abundant intracellular Abeta immunostaining in pyramidal neurons and along axonal tracts. Cases with HIV encephalitis (HIVE) had higher levels of intraneuronal Abeta immunoreactivity compared to HIV+ cases with no HIVE. Moreover, levels of intracellular Abeta correlated with age in the group with HIVE. Double-labeling analysis showed that the Abeta-immunoreactive granules in the neurons co-localized with lysosomal markers such as cathepsin-D and LC3. Ultrastructural analysis by immuno-EM has confirmed that in these cases, intracellular Abeta was often found in structures displaying morphology similar to autophagosomes. These findings suggest that long-term survival with HIV might interfere with clearance of proteins such as Abeta and worsen neuronal damage and cognitive impairment in this population.
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                Author and article information

                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2017
                2 May 2017
                : 2017
                : 3160360
                Affiliations
                1Department of Neurology, First Affiliated Hospital, Guangxi Medical University, Nanning 530021, China
                2Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin 541000, China
                Author notes

                Academic Editor: Anna M. Giudetti

                Author information
                http://orcid.org/0000-0002-9055-9873
                Article
                10.1155/2017/3160360
                5434241
                28553432
                019d8100-31ea-409b-a85c-4fee6868ccd2
                Copyright © 2017 Wenlin Jiang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 November 2016
                : 9 February 2017
                : 1 March 2017
                Funding
                Funded by: National Nature Science Foundation of China
                Award ID: 81371333
                Award ID: 81160152
                Award ID: 2013GXNSFCA019013
                Categories
                Research Article

                Molecular medicine
                Molecular medicine

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