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      Feline Immunodeficiency Virus Neuropathogenesis: A Model for HIV-Induced CNS Inflammation and Neurodegeneration

      1 , * , 2

      Veterinary Sciences

      MDPI

      AIDS, human immunodeficiency virus, dementia, neurons, microglia, macrophages

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Feline Immunodeficiency virus (FIV), similar to its human analog human immunodeficiency virus (HIV), enters the central nervous system (CNS) soon after infection and establishes a protected viral reservoir. The ensuing inflammation and damage give rise to varying degrees of cognitive decline collectively known as HIV-associated neurocognitive disorders (HAND). Because of the similarities to HIV infection and disease, FIV has provided a useful model for both in vitro and in vivo studies of CNS infection, inflammation and pathology. This mini review summarizes insights gained from studies of early infection, immune cell trafficking, inflammation and the mechanisms of neuropathogenesis. Advances in our understanding of these processes have contributed to the development of therapeutic interventions designed to protect neurons and regulate inflammatory activity.

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          Most cited references 147

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          Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors.

          Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.
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            HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors

            Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.
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              The neuropathogenesis of AIDS.

              HIV-associated dementia (HAD) is an important complication of the central nervous system in patients who are infected with HIV-1. Although the incidence of HAD has markedly decreased since it has become possible to effectively control viral replication in the blood by administering highly active antiretroviral therapy, a less severe form of HAD, comprising a milder cognitive and motor disorder, is now potentially a serious problem. Brain macrophages and microglia are the key cell types that are infected by HIV-1 in the central nervous system, and they are likely to mediate the neurodegeneration seen in patients with HAD; however, the precise pathogenesis of this neurodegeneration is still unclear. Here, we discuss the studies that are being carried out to determine the respective contributions of infection, and monocyte and macrophage activation, to disease progression.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Vet Sci
                Vet Sci
                vetsci
                Veterinary Sciences
                MDPI
                2306-7381
                06 March 2017
                March 2017
                : 4
                : 1
                Affiliations
                [1 ]Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
                [2 ]Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA; lola_hudson@ 123456ncsu.edu
                Author notes
                [* ]Correspondence: meekerr@ 123456neurology.unc.edu ; Tel.: +1-919-966-5512
                Article
                vetsci-04-00014
                10.3390/vetsci4010014
                5606611
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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