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Granulocytemacrophage colony-stimulating factor enhances viral load in human brain tissue: amelioration with stavudine

Kandanearatchi, Apsaraa; Zuckerman, Markb; Smith, Melvynb; Vyakarnam, Annapurnac; Everall, Ian P.a

Clinical Science

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is elevated in cerebrospinal fluid in HIV- associated dementia; in addition, therapeutic GM-CSF elevates plasma viral load.

Objective: To assess the effect of GM-CSF on viral replication and the potential ameliorative effect of antiretroviral therapy.

Design: A primary human brain aggregate system is used as a model of the in vivo situation.

Method: Cultured aggregates were infected with the macrophage tropic strain HIV-1SF162 and then exposed to varying GM-CSF concentrations and 0.3 μmol/l stavudine. Viral replication was assessed by p24 expression in the supernatant and aggregates. Immunohistochemistry identified neurons, astrocytes, microglia and oligodendrocytes.

Results: A GM-CSF concentration of 1 ng/ml resulted in a fivefold increase in microglial cells, the main HIV cellular reservoir (P = 0.0001). Prior GM-CSF exposure before infection of the aggregates resulted in sixfold increase in p24 levels compared with non-GM-CSF-exposed infected aggregates. Infected aggregates with or without GM-CSF had significant neuronal loss of 50% and 45%, respectively, and astrocytosis. Addition of stavudine to the infected aggregates, even in the presence of GM-CSF, reduced p24 levels to zero and prevented neuronal loss and astrocytosis.

Conclusions: This study demonstrates that GM-CSF enhances viral replication while addition of stavudine prevents this potentially detrimental process.

From the aInstitute of Psychiatry, King's College, the bSouth London Public Health Laboratory and Department of Infection and the Department of Virology, Guy's, King's and St Thomas’ School of Medicine, King's College Hospital, and the cRayne Institute, Guy's, King's and St Thomas’ Medical School, King's College, London, UK.

Requests for reprints to: Prof. I. P. Everall, Section of Experimental Neuropathology and Psychiatry, Institute of Psychiatry, King's College, DeCrespigny Park, London SE5 8AF, UK.

Received: 15 June 2001;

revised: 27 September 2001; accepted: 3 October 2001.

Sponsorship: A. Kandanaeratchi was supported by an unrestricted educational grant from Bristol Myers Squibb Ltd, UK.

© 2002 Lippincott Williams & Wilkins, Inc.