The Journal of Experimental Medicine
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Published online 21 August 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/587/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 4, August 21, 2000 587-594

Brief Definitive Report

Macrophage-tropic HIV Induces and Exploits Dendritic Cell Chemotaxis

Chen-Lung Lina, Andrew K. Sewellb, George F. Gaob,c, Kathryn T. Whelana,b, Rodney E. Phillipsb, and Jonathan M. Austyna
a Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
b Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
c Structural Molecular Biology Laboratory, Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138

Correspondence to: Andrew K. Sewell, Nuffield Department of Clinical Medicine, Level 7, John Radcliffe Hospital, Oxford OX3 9DU, UK. Tel:44-1865-228927 Fax:44-1865-220993 E-mail:asewell{at}gwmail.jr2.ox.ac.uk.

Immature dendritic cells (iDCs) express the CC chemokine receptor (CCR)5, which promotes chemotaxis toward the CC chemokines regulated on activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1{alpha}, and MIP-1ß. By contrast, mature DCs downregulate CCR5 but upregulate CXC chemokine receptor (CXCR)4, and as a result exhibit enhanced chemotaxis toward stromal cell–derived factor (SDF)-1{alpha}. CCR5 and CXCR4 also function as coreceptors for macrophage-tropic (M-tropic) and T cell–tropic (T-tropic) human immunodeficiency virus (HIV)-1, respectively. Here, we demonstrate chemotaxis of iDCs toward M-tropic (R5) but not T-tropic (X4) HIV-1. Furthermore, preexposure to M-tropic HIV-1 or its recombinant envelope protein prevents migration toward CCR5 ligands. The migration of iDCs toward M-tropic HIV-1 may enhance formation of DC–T cell syncytia, thus promoting viral production and destruction of both DC and T helper lymphocytes. Therefore, disturbance of DC chemotaxis by HIV-1 is likely to contribute to immunosuppression in primary infection and AIDS. In addition, migration of iDCs toward HIV-1 may aid the capture of R5 HIV-1 virions by the abundant DC cell surface protein DC-specific intercellular adhesion molecule (ICAM)3-grabbing nonintegrin (DC-SIGN). HIV-1 bound to DC cell–specific DC-SIGN retains the ability to infect replication-permissive T cells in trans for several days. Consequently, recruitment of DC by HIV-1 could combine with the ability of DC-SIGN to capture and transmit the virus to T cells, and so facilitate dissemination of virus within an infected individual.

Key Words: dendritic cell, HIV, chemotaxis, chemokine, CCR5


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