HIV-1 infection and cognitive impairment in the cART era: a review. AIDS

aDepartment of Neurology, The Netherlands bInternal Medicine, Division of Infectious Diseases, Tropical Medicine & Aids, Academic Medical Center, Amsterdam, The Netherlands cCenter for Poverty-related Communicable Diseases, Academic Medical Center and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands dDepartment of Neurology, OLVG Hospital, Amsterdam, The Netherlands eDepartment of Infectious Diseases, San Rafaele Scientific Institute, Milan, Italy fDepartment of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.
AIDS (London, England) (Impact Factor: 5.55). 12/2010; 25(5):561-75. DOI: 10.1097/QAD.0b013e3283437f9a
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With the introduction of combination antiretroviral therapy AIDS dementia complex or HIV-associated dementia, as it was termed later, largely disappeared in clinical practice. However, in the past few years, patients, long-term infected and treated, including those with systemically well controlled infection, started to complain about milder memory problems and slowness, difficulties in concentration, planning, and multitasking. Neuropsychological studies have confirmed that cognitive impairment occurs in a substantial (15-50%) proportion of patients. Among HIV-1-infected patients cognitive impairment was and is one of the most feared complications of HIV-1 infection. In addition, neurocognitive impairment may affect adherence to treatment and ultimately result in increased morbidity for systemic disease. So what may be going on in the CNS after so many years of apparently controlled HIV-1 infection is an urgent and important challenge in the field of HIV medicine. In this review we summarize the key currently available data. We describe the clinical neurological and neuropsychological findings, the preferred diagnostic approach with new imaging techniques and cerebrospinal fluid analysis. We try to integrate data on pathogenesis and finally discuss possible therapeutic interventions.

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Available from: Paola Cinque, Nov 23, 2014
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    • "As of 2012, the Word Health Organization estimates that approximately 35 million people are living with human immunodeficiency virus (HIV). Out of these, 30–60 % are expected to develop some form of HIV-associated neurocognitive disorder (HAND) despite treatment with antiretroviral therapy (cART) (Schouten et al. 2011). Novel biomarkers detectable in human biological fluids, such as blood, plasma, saliva, or cerebral spinal fluid (CSF), are needed to support earlier clinical diagnosis of HAND (reviewed in (Price et al. 2013)). "
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    ABSTRACT: We identified and measured proteins in the cerebral spinal fluid (CSF) involved in HIV-associated neurological disorders. Protein levels were determined by mass spectrometry (MS) in pooled CSF taken from three patient groups (human immunodeficiency virus (HIV)-1-infected patients that developed HIV-associated neurocognitive disorders (HANDs), HIV-1-infected patients without HAND, and healthy controls). Pools were generated from 10 patients each per group. CSF from individual patient groups were digested with trypsin and separately labeled using with isobaric tags for relative and absolute quantitation (iTRAQ). After combining all samples in one, peptides were extensively fractionated by offline two-dimensional separation and identified by tandem MS. One hundred and ninety three proteins were deemed to be interpretable for quantitation based on permutation tests with a 95 % confidence interval with a p value ≤ 0.05. Using a cutoff of 1.5-fold for upregulation and 0.6 for downregulation, 16 proteins were differentially expressed in HIV + HAND (reporter p value ≤0.05) with seven of them previously described as HIV-interacting proteins: endoplasmin, mitochondrial damage mediator-BH3-interacting domanin death agonist, orosomucoid, apolipoprotein E, metalloproteinase inhibitor 2, peroxiredoxin-2, and the nuclear protein, ruvB-like 2. Several previously unidentified proteins with possible neurological implication in HIV patients include forming-binding protein 1, C-reactive protein, leukocyte-associated immunoglobulin receptor 1, renin receptor, mediator of RNA polymerase II transcription subunit 14, multimerin-2, alpha-N-acetylglucosaminidase, caldesmon, and cadherin EGF LAG G-type receptor. Our results suggest that not only a few but possibly a combination of biomarkers that are highly correlated can predict neurocognitive status in HIV-infected patients and might be involved in monocyte or macrophage activation.
    Journal of NeuroVirology 07/2014; 20(5). DOI:10.1007/s13365-014-0263-5 · 2.60 Impact Factor
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    • "For instance, it might be the result of a process that has been going on for years, or it might be the exitus of a subacute deterioration in which viral control in the CNS is suddenly lost. As reported by Schouten et al. (2011), we still do not know whether such deterioration will strike each HIV-infected hemophiliac, or a subset of patients at risk. Such a review can give us insight into the literature and compare different results in different cohorts of patients, but at the same time, many aspects about the neurology system in these patients are an unknown. "
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    ABSTRACT: The debate regarding neurocognitive functions in the early stages of HIV infection is still ongoing; different studies have reached contrasting conclusions, probably because many of them take into account different cohorts of patients. A main distinction is between HIV seropositive patients infected perinatally, and those infected postnatally. The aim of this paper is to review results on neurocognitive dysfunctions and other types of neurological involvement in a specific cohort of HIV+ patients infected postnatally: hemophilia patients. Such a review is relevant, as HIV seropositive patients infected postnatally are understudied with respect to patients infected perinatally, and as the results of the few studies aiming at comparing them are contrasting. Taken together, the 11 studies reviewed suggest the presence of both long-term neurocognitive dysfunctions and neurological alterations, such as the presence of atrophic changes and lesions in the white matter. The current review may offer new research insights into the neurocognitive dysfunctions in HIV-patients, and on the nature of such dysfunctions.
    Frontiers in Human Neuroscience 06/2014; 8. DOI:10.3389/fnhum.2014.00470 · 3.63 Impact Factor
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    • "Neurologic disorders associated with HIV-1 infection occur in about 40% to 70% of HIV-infected individuals [3]. Despite the improved life expectancy of HIV-1-infected patients due to the advent of highly active antiretroviral therapy (HAART there is an increased prevalence of neurocognitive impairment infected individuals [4]–[7]. Part of this increase may be attributed to poor penetration of HAART drugs into the CNS to eradicate the virus [8] and increased life expectancy of HIV-1-infected patients. "
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    ABSTRACT: HIV-1 associated dementia remains a significant public health burden. Clinical and experimental research has shown that reduced levels of brain-derived neurotrophic factor (BDNF) may be a risk factor for neurological complications associated with HIV-1 infection. We are actively testing genetically modified macrophages for their possible use as the cell-based gene delivery vehicle for the central nervous system (CNS). It can be an advantage to use the natural homing/migratory properties of monocyte-derived macrophages to deliver potentially neuroprotective BDNF into the CNS, as a non-invasive manner. Lentiviral-mediated gene transfer of human (h)BDNF plasmid was constructed and characterized. Defective lentiviral stocks were generated by transient transfection of 293T cells with lentiviral transfer plasmid together with packaging and envelope plasmids. High titer lentiviral vector stocks were harvested and used to transduce human neuronal cell lines, primary cultures of human peripheral mononocyte-derived macrophages (hMDM) and murine myeloid monocyte-derived macrophages (mMDM). These transduced cells were tested for hBDNF expression, stability, and neuroprotective activity. The GenomeLab GeXP Genetic Analysis System was used to evaluate transduced cells for any adverse effects by assessing gene profiles of 24 reference genes. High titer vectors were prepared for efficient transduction of neuronal cell lines, hMDM, and mMDM. Stable secretion of high levels of hBDNF was detected in supernatants of transduced cells using western blot and ELISA. The conditioned media containing hBDNF were shown to be protective to neuronal and monocytic cell lines from TNF-α and HIV-1 Tat mediated cytotoxicity. Lentiviral vector-mediated gene transduction of hMDM and mMDM resulted in high-level, stable expression of the neuroprotective factorBDNF in vitro. These findings form the basis for future research on the potential use of BDNF as a novel therapy for neuroAIDS.
    PLoS ONE 02/2014; 9(2):e82030. DOI:10.1371/journal.pone.0082030 · 3.23 Impact Factor
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