Hiv-Associated Neurocognitive Disease: Case Studies and Suggestions for Diagnosis and Management in Different Patient Subgroups

Pozniak, Anton; Rackstraw, Simon; Deayton, Jane R; Barber, Tristan; Taylor, Stephen; Manji, Hadi; Melvin, Diane; Croston, Michelle; Nightingale, Sam; Kulasegaram, Ranubabu; Pitkänen, Mikko R. A.; Winston, Alan

doi:10.3851/imp2563

Cited by 10 publications

(6 citation statements)

References 71 publications

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“…Persistent HIV-1 infection commonly leads to cognitive, behavioral and motor abnormalities called HIV-associated neurocognitive disorders (HAND) [ 1 – 3 ]. Despite intensive research, investigations seeking virus-associated central nervous system (CNS) biomarkers and HAND therapies have failed, in measure, due to the multifactorial nature of disease and by few relevant small animal models [ 4 – 6 ]. The obstacles in generating a small animal model require that viral tropism, neuroimmune activation, cognitive impairments and CD4 + T cell losses are operative [ 1 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice

Boska

Dash

Knibbe

et al. 2014

Mol Neurodegeneration

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BackgroundHost-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rgcnull mice transplanted with human CD34+ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus.MethodsChanges in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens.ResultsBehavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum.ConclusionsThe findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-58) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice

Boska

Dash

Knibbe

et al. 2014

Mol Neurodegeneration

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“…The neuropathogenesis of HAND remains incompletely understood; it may overlap that of other common neurodegenerative diseases in which genetics has a role and with which HAND shares certain similarities [16, 17•, 18•, 19, 20•]. Recognition of the critical importance of neuro-inflammation, reflected by elevated expression of inflammation or immune-activation biomarkers in the brain, cerebrospinal fluid (CSF) and in some cases, plasma in HAND [21–23], and the central role played by mononuclear phagocytes in these disorders, has provided a framework for studies of the role of host genetic variation in HAND to date [18•, 24•, 25•].…”

Section: Introductionmentioning

confidence: 99%

Host Genetic Factors Predisposing to HIV-Associated Neurocognitive Disorder

Kallianpur

Levine

2014

Curr HIV/AIDS Rep

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The success of combination antiretroviral therapy (cART) in transforming the lives of HIV-infected individuals with access to these drugs is tempered by the increasing threat of HIV-associated neurocognitive disorders (HAND) to their overall health and quality of life. Intensive investigations over the past two decades have underscored the role of host immune responses, inflammation, and monocyte-derived macrophages in HAND, but the precise pathogenic mechanisms underlying HAND remain only partially delineated. Complicating research efforts and therapeutic drug development are the sheer complexity of HAND phenotypes, diagnostic imprecision, and the growing intersection of chronic immune activation with aging-related comorbidities. Yet, genetic studies still offer a powerful means of advancing individualized care for HIV-infected individuals at risk. There is an urgent need for 1) longitudinal studies using consistent phenotypic definitions of HAND in HIV-infected subpopulations at very high risk of being adversely impacted, such as children, 2) tissue studies that correlate neuropathological changes in multiple brain regions with genomic markers in affected individuals and with changes at the RNA, epigenomic, and/or protein levels, and 3) genetic association studies using more sensitive subphenotypes of HAND. The NIH Brain Initiative and Human Connectome Project, coupled with rapidly evolving systems biology and machine learning approaches for analyzing high-throughput genetic, transcriptomic and epigenetic data, hold promise for identifying actionable biological processes and gene networks that underlie HAND. This review summarizes the current state of understanding of host genetic factors predisposing to HAND in light of past challenges and suggests some priorities for future research to advance the understanding and clinical management of HAND in the cART era.

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“…Demografische Kofaktoren sind Alter [3], mangelnde Bildung sowie fehlender Zugang zu den modernen antiretroviralen Therapien [15]. Direkt virusassoziierte Kofaktoren sind: lange Dauer der HIV-Positivität, niedriger CD4 + -Zell-Nadir, niedrige aktuelle CD4 + -Zellzahlen [16], eine hohe Plasma-Viruslast [17] und zerebrale, opportunistische Infektionen in der Vorgeschichte [18]. Shiramizu et al fanden eine gute Korrelation zwischen HAND und der Virus-DNA in infizierten Monozyten [19], therapieassoziierte Kofaktoren sind: niedrige Therapietreue, suboptimale Behandlung mit im Blut und/oder Liquor nachweisbarer Viruslast bzw.…”

Section: Kofaktorenunclassified

Neues bei HIV und Neuro-Aids

et al. 2015

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Zusammenfassung Trotz sehr effektiver Behandlungsoptionen f?r die systemische HIV-Infektion sind Neuro-Aids und die HIV-assoziierte neurokognitive St?rung ein klinisches und alltagsrelevantes Problem. Man unterscheidet 3 Stufen, das HIV-assoziierte, neuropsychologische Defizit (ANPD), das milde, HIV-assoziierte neurokognitive Defizit (MNCD) und die HIV-assoziierte Demenz (HAD). Die Behandlungsm?glichkeiten HIV-assoziierter neuro-kognitiver St?rungen umfasst die antiretrovirale Therapie (cART), die den CPE-Score zur Penetration der Medikamente ins ZNS ber?cksichtigen sollte. Es ist sinnvoll, bei Auftreten multiresistenter Virusvarianten im Blut auch im Liquor entsprechende Untersuchungen durchzuf?hren. Im peripheren Nervensystems treten neben der klassischen, distal-symmetrischen, HIV-assoziierten Polyneuropathie immunogen vermittelte Neuropathien oder Myopathien auf (CIDP, AIDP). Durch die antiretrovirale Therapie (cART) verursachte Polyneuropathien sind differenzialdiagnostisch zu ber?cksichtigen. Erworbene mitochondrial toxische Myopathien treten h?ufiger auf, da nun eine cART durchaus ?ber 10???20 Jahre durchgef?hrt wird. Bei Patienten mit schweren depressiven Episoden zeigte sich eine 6-mal h?here Wahrscheinlichkeit, die Einnahme der cART mindestens einmal zu vergessen. Depressive Episoden sind oft ein Grund f?r mangelhafte Adh?renz, korrelieren mit einer h?heren Viruslast und sind dringend zu behandeln. In den letzten Jahren kam es infolge der verbesserten cART zu einem R?ckgang der opportunistischen Infektionen (OI) des ZNS. Die h?ufigsten OI stellen die progressive multifokale Leukoenzephalopathie (PML), die Toxoplasma-Enzephalitis und die Kryptokokken-Meningitis dar. Bei rasch progredientem Verlauf einer OI muss an ein Immunrekonstitutionssyndrom (IRIS) gedacht werden. Es gibt momentan keine sichere Methode, z.?B. die Verschlechterung einer PML durch den nat?rlichen Krankheitsverlauf von der Verschlechterung durch ein IRIS zu unterscheiden. Infolge der deutlich zunehmenden Lebenserwartung treten Komorbidit?ten mehr in den Vordergrund. Zu den viralen Biomarkern f?r die Krankheitsaktivit?t im ZNS z?hlen Neopterin als Marker der Makrophagenaktivierung, das Neurofilament-Leichtprotein und das Gesamt-Tau-Protein.

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Hiv-Associated Neurocognitive Disease: Case Studies and Suggestions for Diagnosis and Management in Different Patient Subgroups

Cited by 10 publications

References 71 publications

Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice

Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice

Host Genetic Factors Predisposing to HIV-Associated Neurocognitive Disorder

Neues bei HIV und Neuro-Aids

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