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J Virol, April 1998, p. 3351-3361, Vol. 72, No. 4
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Role of the beta -Chemokine Receptors CCR3 and CCR5 in Human Immunodeficiency Virus Type 1 Infection of Monocytes and Microglia

Anuja Ghorpade,1 Meng Qi Xia,2 Bradley T. Hyman,2 Yuri Persidsky,1 Adeline Nukuna,1 Paul Bock,1 Myhanh Che,1 Jenae Limoges,1 Howard E. Gendelman,1,* and Charles R. Mackay3,dagger

Center for Neurovirology and Neurodegenerative Disorders and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 681981; Alzheimer's Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 021142; and LeukoSite Inc., Cambridge, Massachusetts 021423

Received 28 August 1997/Accepted 30 December 1997

Human immunodeficiency virus type 1 (HIV-1) infection in mononuclear phagocyte lineage cells (monocytes, macrophages, and microglia) is a critical component in the pathogenesis of viral infection. Viral replication in macrophages serves as a reservoir, a site of dissemination, and an instigator for neurological sequelae during HIV-1 disease. Recent studies demonstrated that chemokine receptors are necessary coreceptors for HIV-1 entry which determine viral tropism for different cell types. To investigate the relative contribution of the beta -chemokine receptors CCR3 and CCR5 to viral infection of mononuclear phagocytes we utilized a panel of macrophage-tropic HIV-1 strains (from blood and brain tissue) to infect highly purified populations of monocytes and microglia. Antibodies to CD4 (OKT4A) abrogated HIV-1 infection. The beta  chemokines and antibodies to CCR3 failed to affect viral infection of both macrophage cell types. Antibodies to CCR5 (3A9) prevented monocyte infection but only slowed HIV replication in microglia. Thus, CCR5, not CCR3, is an essential receptor for HIV-1 infection of monocytes. Microglia express both CCR5 and CCR3, but antibodies to them fail to inhibit viral entry, suggesting the presence of other chemokine receptors for infection of these cells. These studies demonstrate the importance of mononuclear phagocyte heterogeneity in establishing HIV-1 infection and persistence.

* Corresponding author. Mailing address: Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Box 985215, 600 S. 42nd St., Omaha, NE 68198-5215. Phone: (402) 559-8920. Fax: (402) 559-8922. E-mail: hegendel{at}mail.unmc.edu.

dagger Present address: Millennium Biotherapeutics, Cambridge, MA 02139.




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