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Journal of Virology, February 2003, p. 2550-2558, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2550-2558.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

G Protein-Dependent CCR5 Signaling Is Not Required for Efficient Infection of Primary T Lymphocytes and Macrophages by R5 Human Immunodeficiency Virus Type 1 Isolates

Ali Amara,1* Aurore Vidy,1 Genevieve Boulla,2 Karine Mollier,3 Javier Garcia-Perez,4 Jose Alcamí,4 Cedric Blanpain,5 Marc Parmentier,5 Jean-Louis Virelizier,1 Pierre Charneau,3 and Fernando Arenzana-Seisdedos1

Unité d'Immunologie Virale,1 Groupe de Virologie Moléculaire et Vectorologie, Institut Pasteur,3 CNRS UPR415, Paris, France,2 AIDS Immunopathogenesis Unit, Centro Nacional de Microbiologia, Madrid, Spain,4 Institute of Interdisciplinary Research, Université Libre de Bruxelles, Brussels, Belgium5

Received 24 July 2002/ Accepted 12 November 2002

The requirement of human immunodeficiency virus (HIV)-induced CCR5 activation for infection by R5 HIV type 1 (HIV-1) strains remains controversial. Ectopic CCR5 expression in CD4+-transformed cells or pharmacological inhibition of G{alpha}i proteins coupled to CCR5 left unsolved whether CCR5-dependent cell activation is necessary for the HIV life cycle. In this study, we investigated the role played by HIV-induced CCR5-dependent cell signaling during infection of primary CD4-expressing leukocytes. Using lentiviral vectors, we restored CCR5 expression in T lymphocytes and macrophages from individuals carrying the homozygous 32-bp deletion of the CCR5 gene (ccr5 {Delta}32/{Delta}32). Expression of wild-type (wt) CCR5 in ccr5 {Delta}32/{Delta}32 cells permitted infection by R5 HIV isolates. We assessed the capacity of a CCR5 derivative carrying a mutated DRY motif (CCR5-R126N) in the second intracellular loop to work as an HIV-1 coreceptor. The R126N mutation is known to disable G protein coupling and agonist-induced signal transduction through CCR5 and other G protein-coupled receptors. Despite its inability to promote either intracellular calcium mobilization or cell chemotaxis, the inactive CCR5-R126N mutant provided full coreceptor function to several R5 HIV-1 isolates in primary cells as efficiently as wt CCR5. We conclude that in a primary, CCR5-reconstituted CD4+ cell environment, G protein signaling is dispensable for R5 HIV-1 isolates to actively infect primary CD4+ T lymphocytes or macrophages.

* Corresponding author. Mailing address: Unité d'Immunologie Virale, Institut Pasteur, F-75724 Paris Cedex 15, France. Phone: 33 (0)1 40 61 31 97. Fax: 33 (0)1 45 68 89 41. E-mail: aamara{at}pasteur.fr.

Journal of Virology, February 2003, p. 2550-2558, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2550-2558.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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