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Journal of Virology, September 2000, p. 7794-7802, Vol. 74, No. 17
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Synthetic Immunomodulator Murabutide Controls Human Immunodeficiency Virus Type 1 Replication at Multiple Levels in Macrophages and Dendritic Cells

Edith C. A. Darcissac,1,2 Marie-José Truong,2 Joëlle Dewulf,2 Yves Mouton,3 André Capron,1 and George M. Bahr1,2,*

Laboratoire d'Immunologie Moléculaire de l'Infection et de l'Inflammation, Institut Pasteur de Lille,1 and ISTAC Biotechnology,2 Lille, and Service des Maladies Infectieuses, Hôpital Dron, Tourcoing3 France

Received 5 April 2000/Accepted 9 June 2000

Macrophages and dendritic cells are known to play an important role in the establishment and persistence of human immunodeficiency virus (HIV) infection. Besides antiretroviral therapy, several immune-based interventions are being evaluated with the aim of achieving better control of virus replication in reservoir cells. Murabutide is a safe synthetic immunomodulator presenting a capacity to enhance nonspecific resistance against viral infections and to target cells of the reticuloendothelial system. In this study, we have examined the ability of Murabutide to control HIV type 1 (HIV-1) replication in acutely infected monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs). Highly significant suppression of viral replication was consistently observed in Murabutide-treated cultures of both cell types. Murabutide did not affect virus entry, reverse transcriptase activity, or early proviral DNA formation in the cytoplasm of infected cells. However, treated MDMs and MDDCs showed a dramatic reduction in nuclear viral two-long terminal repeat circular form and viral mRNA transcripts. This HIV-1-suppressive activity was not mediated by inhibiting cellular DNA synthesis or by activating p38 mitogen-activated protein kinase. Furthermore, Murabutide-stimulated cells expressed reduced CD4 and CCR5 receptors and secreted high levels of beta -chemokines, although neutralization of the released chemokines did not alter the HIV-1-suppressive activity of Murabutide. These results provide evidence that a clinically acceptable immunomodulator can activate multiple effector pathways in macrophages and in dendritic cells, rendering them nonpermissive for HIV-1 replication.

* Corresponding author. Mailing address: Laboratoire d'Immunologie Moléculaire de l'Infection et de l'Inflammation, Institut Pasteur de Lille, 1, rue du Professeur Calmette, B.P. 245, 59019 Lille Cedex, France. Phone: (33) 3 20 87 72 91. Fax: (33) 3 20 87 72 92. E-mail: georges.bahr{at}pasteur-lille.fr.

Journal of Virology, September 2000, p. 7794-7802, Vol. 74, No. 17
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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