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      HIV-Associated Neurocognitive Impairment in the Modern ART Era: Are We Close to Discovering Reliable Biomarkers in the Setting of Virological Suppression?

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          Abstract

          The prevalence of the most severe forms of HIV-associated neurocognitive disorders (HAND) is decreasing due to worldwide availability and high efficacy of antiretroviral treatment (ART). However, several grades of HIV-related cognitive impairment persist with effective ART and remain a clinical concern for people with HIV (PWH). The pathogenesis of these cognitive impairments has yet to be fully understood and probably multifactorial. In PWH with undetectable peripheral HIV-RNA, the presence of viral escapes in cerebrospinal fluid (CSF) might explain a proportion of cases, but not all. Many other mechanisms have been hypothesized to be involved in disease progression, in order to identify possible therapeutic targets. As potential indicators of disease staging and progression, numerous biomarkers have been used to characterize and implicate chronic inflammation in the pathogenesis of neuronal injuries, such as certain phenotypes of activated monocytes/macrophages, in the context of persistent immune activation. Despite none of them being disease-specific, the correlation of several CSF cellular biomarkers to HIV-induced neuronal damage has been investigated. Furthermore, recent studies have been evaluating specific microRNA (miRNA) profiles in the CSF of PWH with neurocognitive impairment (NCI). The aim of the present study is to review the body of evidence on different biomarkers use in research and clinical settings, focusing on PWH on ART with undetectable plasma HIV-RNA.

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          The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility.

          Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1alphaP), a potent human immunodeficiency virus-1 (HIV-1)-suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.
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            Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity

            Tumor necrosis factor alpha (TNF- α ) is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF- α ; this de novo production of TNF- α is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF- α can potentiate glutamate-mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca+2 permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAA receptors on neurons. Thus, the net effect of TNF- α is to alter the balance of excitation and inhibition resulting in a higher synaptic excitatory/inhibitory ratio. This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF- α links the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS). As microglial activation and upregulation of TNF- α expression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF- α signaling may represent a valuable target for intervention.
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              Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE.

              Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                02 August 2019
                2019
                : 11
                : 187
                Affiliations
                [1] 1Infectious Disease Unit, Department of Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy
                [2] 2Department of Pathophysiology and Transplantation, University of Milano , Milan, Italy
                [3] 3Infectious Diseases Clinic, Department of Health Sciences, School of Medical and Pharmaceutical Sciences, Policlinico Hospital San Martino, University of Genova (DISSAL) , Genova, Italy
                [4] 4Department of Neuroscience, Lewis Katz School of Medicine at Temple University , Philadelphia, PA, United States
                Author notes

                Edited by: Wee Shiong Lim, Tan Tock Seng Hospital, Singapore

                Reviewed by: Rachel Dara Schrier, University of California, San Diego, United States; James Alan Bourgeois, Baylor Scott and White Health, United States

                *Correspondence: Alessandra Bandera alessandra.bandera@ 123456unimi.it

                These authors have contributed equally to this work

                Article
                10.3389/fnagi.2019.00187
                6687760
                31427955
                a5a00cf1-189b-4e32-b5e0-ef3d59ca4ef8
                Copyright © 2019 Bandera, Taramasso, Bozzi, Muscatello, Robinson, Burdo and Gori.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 April 2019
                : 10 July 2019
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 114, Pages: 20, Words: 16499
                Categories
                Neuroscience
                Review

                Neurosciences
                marker,neurocognitive impairment,hiv,art,ani,hand,aids,dementia
                Neurosciences
                marker, neurocognitive impairment, hiv, art, ani, hand, aids, dementia

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