Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS
Kenneth Williams, … , Eliezer Masliah, R. Gilberto González
Kenneth Williams, … , Eliezer Masliah, R. Gilberto González
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2534-2545. https://doi.org/10.1172/JCI22953.
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Research Article Virology

Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS

Abstract

Difficulties in understanding the mechanisms of HIV neuropathogenesis include the inability to study dynamic processes of infection, cumulative effects of the virus, and contributing host immune responses. We used 1H magnetic resonance spectroscopy and studied monocyte activation and progression of CNS neuronal injury in a CD8 lymphocyte depletion model of neuroAIDS in SIV-infected rhesus macaque monkeys. We found early, consistent neuronal injury coincident with viremia and SIV infection/activation of monocyte subsets and sought to define the role of plasma virus and monocytes in contributing to CNS disease. Antiretroviral therapy with essentially non–CNS-penetrating agents resulted in slightly decreased levels of plasma virus, a significant reduction in the number of activated and infected monocytes, and rapid, near-complete reversal of neuronal injury. Robust macrophage accumulation and productive virus replication were found in brains of infected and CD8 lymphocyte–depleted animals, but no detectable virus and few scattered infiltrating macrophages were observed in CD8 lymphocyte–depleted animals compared with animals not receiving antiretroviruses that were sacrificed at the same time after infection. These results underscore the role of activated monocytes and monocyte infection outside of the brain in driving CNS disease.

Authors

Kenneth Williams, Susan Westmoreland, Jane Greco, Eva Ratai, Margaret Lentz, Woong-Ki Kim, Robert A. Fuller, John P. Kim, Patrick Autissier, Prahbat K. Sehgal, Raymond F. Schinazi, Norbert Bischofberger, Michael Piatak Jr., Jeffrey D. Lifson, Eliezer Masliah, R. Gilberto González

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Expansion of monocyte populations following SIV infection and CD8 lympho...
Expansion of monocyte populations following SIV infection and CD8 lymphocyte depletion and analysis of monocyte-associated SIV RNA and DNA. (A) The percentage of monocytes that coexpress CD16 was assayed as a function of time after infection. Two populations of activated monocytes were assessed: CD14+ monocytes that coexpressed CD16 (CD14+CD16+) and CD14lowCD16high monocytes. Peaks in the percentage of both populations were observed between 7 and 14 days after infection. A second increase in the percentage of both populations was observed prior to or with the development of AIDS. **P < 0.05 and *P < 0.1 vs. day 0; paired Student’s t test. (B) SIV RNA was assessed in FACS-sorted populations of CD14highCD16low and CD14lowCD16high monocytes. In both populations, there was an initial peak in the level of SIV RNA between 7 and 14 days after infection, followed by a decline and a subsequent increase prior to or coincident with the development of AIDS. (C) SIV DNA was assessed in FACS-sorted populations of CD14highCD16low and CD14lowCD16high monocytes. In both populations, there was a peak in the level of SIV DNA 7–14 days after infection and another peak with the development of AIDS. The CD14lowCD16high population was consistently SIV DNA positive. The hatched line represents the lower detection limit of the PCR assay.