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      Microglial HIV-1 Expression: Role in HIV-1 Associated Neurocognitive Disorders

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          Abstract

          The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to (1) evaluate the HIV-1 mRNA distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat, and (2) validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 h of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results that are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments and synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway and/or neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

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            Microglia and neuroinflammation: a pathological perspective

            Microglia make up the innate immune system of the central nervous system and are key cellular mediators of neuroinflammatory processes. Their role in central nervous system diseases, including infections, is discussed in terms of a participation in both acute and chronic neuroinflammatory responses. Specific reference is made also to their involvement in Alzheimer's disease where microglial cell activation is thought to be critically important in the neurodegenerative process.
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              Synaptic density in human frontal cortex - developmental changes and effects of aging.

              Density of synaptic profiles in layer 3 of middle frontal gyrus was quantitated in 21 normal human brains ranging from newborn to age 90 years. Synaptic profiles could be reliably demonstrated by the phosphotungstic acid method (Bloom and Aghajanian) in tissue fixed up to 36 h postmortem. Synaptic density was constant throughout adult life (ages 16--72 years) with a mean of 11.05 X 10(8) synapses/cu.mm +/- 0.41 S.E.M. There was a slight decline in synaptic density in brains of the aged (ages 74--90 years) with a mean of 9.56 X 10(8) synapses/cu.mm +/- 0.28 S.E.M. in 4 samples (P less than 0.05). Synaptic density in neonatal brains was already high--in the range seen in adults. However, synaptic morphology differed; immature profiles had an irregular presynaptic dense band instead of the separate presynaptic projections seen in mature synapses. Synaptic density increased during infancy, reaching a maximum at age 1--2 years which was about 50% above the adult mean. The decline in synaptic density observed between ages 2--16 years was accompanied by a slight decrease in neuronal density. Human cerebral cortex is one of a number of neuronal systems in which loss of neurons and synapses appears to occur as a late developmental event.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                17 May 2021
                May 2021
                : 13
                : 5
                : 924
                Affiliations
                Department of Psychology, University of South Carolina, Columbia, SC 29208, USA; hailong@ 123456mailbox.sc.edu (H.L.); mclaurik@ 123456email.sc.edu (K.A.M.); illenber@ 123456email.sc.edu (J.M.I.); mactutus@ 123456mailbox.sc.edu (C.F.M.)
                Author notes
                [* ]Correspondence: booze@ 123456mailbox.sc.edu
                Article
                viruses-13-00924
                10.3390/v13050924
                8155894
                35062217
                a52e0c4b-5b0f-491e-984f-47f5be0d3b62
                © 2021 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 ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 26 March 2021
                : 11 May 2021
                Categories
                Article

                Microbiology & Virology
                ecohiv,hiv,hand,microglia,rnascope,viral reservoir
                Microbiology & Virology
                ecohiv, hiv, hand, microglia, rnascope, viral reservoir

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