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Central Nervous System Inflammation and Infection During Early, Non-Accelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques.

Central Nervous System Inflammation and Infection During Early, Non-Accelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques.
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Hsu DC, Sunyakumthorn P, Wegner M, Schuetz A, Silsorn D, Estes JD, Deleage C, Tomusange K, Lakhashe SK, Ruprecht RM, Lombardini E, Im-Erbsin R, Kuncharin Y, Phuang-Ngern Y, Inthawong D, Chuenarom W, Burke R, Robb ML, Ndhlovu LC, Ananworanich J, Valcour V, O'Connell RJ, Spudich S, Michael NL, Vasan S,


Hsu DC, Sunyakumthorn P, Wegner M, Schuetz A, Silsorn D, Estes JD, Deleage C, Tomusange K, Lakhashe SK, Ruprecht RM, Lombardini E, Im-Erbsin R, Kuncharin Y, Phuang-Ngern Y, Inthawong D, Chuenarom W, Burke R, Robb ML, Ndhlovu LC, Ananworanich J, Valcour V, O'Connell RJ, Spudich S, Michael NL, Vasan S, (click to view)

Hsu DC, Sunyakumthorn P, Wegner M, Schuetz A, Silsorn D, Estes JD, Deleage C, Tomusange K, Lakhashe SK, Ruprecht RM, Lombardini E, Im-Erbsin R, Kuncharin Y, Phuang-Ngern Y, Inthawong D, Chuenarom W, Burke R, Robb ML, Ndhlovu LC, Ananworanich J, Valcour V, O'Connell RJ, Spudich S, Michael NL, Vasan S,

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Journal of virology 2018 03 21() pii 10.1128/JVI.00222-18

Abstract

Studies utilizing highly pathogenic simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) have largely focused on the immunopathology of the central nervous system (CNS) during end-stage neuro AIDS and SIV encephalitis. However, this may not model pathophysiology in earlier stages of infection. In this non-accelerated SHIV model, plasma SHIV RNA levels and peripheral blood and colonic CD4 T+ cell counts mirrored early HIV infection in humans. At 12 weeks post infection, cerebrospinal fluid (CSF) detection of SHIV RNA and elevations in IP-10 and MCP-1 reflected a discrete neurovirologic process. Immunohistochemical staining revealed a diffuse, low-level CD3+, CD4- cellular infiltrate in the brain parenchyma, without a concomitant increase in CD68/CD163+ monocytes, macrophages and activated microglial cells. Rare SHIV-infected cells in the brain parenchyma and meninges were identified by RNAscopehybridization. In the meninges, there was also a trend toward increased CD4+ infiltration in SHIV-infected animals, but no differences in CD68/CD163+ cells between SHIV-infected and uninfected control animals. These data suggest that in a model that closely recapitulates human disease, CNS inflammation and SHIV in CSF may be predominantly mediated by T-cell mediated processes during early infection in both brain parenchyma and meninges. Because SHIV expresses an HIV rather than SIV envelope, this model could inform studies to understand potential HIV cure strategies targeting the HIV envelope.Animal models of the neurologic effects of HIV are needed because brain pathology is difficult to assess in humans. Many current models focus on the effects of late stage disease utilizing simian immunodeficiency virus (SIV). In the era of antiretroviral therapy, manifestations of late stage HIV are less common. Furthermore, new interventions such as monoclonal antibodies and therapeutic vaccinations target HIV envelope. We therefore describe a new model of central nervous system involvement in rhesus macaques infected with simian-human immunodeficiency virus (SHIV) expressing HIV envelope in earlier, less aggressive stages of disease. Here, we demonstrate that SHIV mimics the early clinical course in humans, and that early neurologic inflammation is characterized by predominantly T cell mediated inflammation, accompanied by SHIV infection in the brain and meninges. This model can be utilized to assess the effect of novel therapies targeted to HIV envelope on reducing brain inflammation before end stage disease.

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