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Journal of Virology, July 2006, p. 6487-6496, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02539-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Recombinant Extracellular Domains of Tetraspanin Proteins Are Potent Inhibitors of the Infection of Macrophages by Human Immunodeficiency Virus Type 1

Siu-Hong Ho,1 Francine Martin,2,3 Adrian Higginbottom,2 Lynda J. Partridge,3 Varadarajan Parthasarathy,3 Gregory W. Moseley,3,§ Peter Lopez,1 Cecilia Cheng-Mayer,1*,{dagger} and Peter N. Monk2,{dagger}

Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, 7th Floor, New York, New York 10016,1 Academic Neurology Unit, University of Sheffield Medical School, Sheffield S10 2RX, United Kingdom,2 Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, United Kingdom3

Received 5 December 2005/ Accepted 11 April 2006

Human immunodeficiency virus type 1 (HIV-1) infection of human macrophages can be inhibited by antibodies which bind to the tetraspanin protein CD63, but not by antibodies that bind to other members of the tetraspanin family. This inhibitory response was limited to CCR5 (R5)-tropic virus and was only observed using macrophages, but not T cells. Here, we show that recombinant soluble forms of the large extracellular domain (EC2) of human tetraspanins CD9, CD63, CD81, and CD151 produced as fusion proteins with glutathione S-transferase (GST) can all potently and completely inhibit R5 HIV-1 infection of macrophages with 50% inhibitory concentration values of 0.11 to 1.2 nM. Infection of peripheral blood mononuclear cells could also be partly inhibited, although higher concentrations of EC2 proteins were required. Inhibition was largely coreceptor independent, as macrophage infections by virions pseudotyped with CXCR4 (X4)-tropic HIV-1 or vesicular stomatitis virus (VSV)-G glycoproteins were also inhibited, but was time dependent, since addition prior to or during, but not after, virus inoculation resulted in potent inhibition. Incubation with tetraspanins did not decrease CD4 or HIV-1 coreceptor expression but did block virion uptake. Colocalization of fluorescently labeled tetraspanin EC2 proteins and HIV-1 virions within, and with CD4 and CXCR4 at the cell surfaces of, macrophages could be detected, and internalized tetraspanin EC2 proteins were directed to vesicular compartments that contained internalized dextran and transferrin. Collectively, the data suggest that the mechanism of inhibition of HIV-1 infection by tetraspanins is at the step of virus entry, perhaps via interference with binding and/or the formation of CD4-coreceptor complexes within microdomains that are required for membrane fusion events.

* Corresponding author. Mailing address: Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, 7th Floor, New York, NY 10016. Phone: (212) 448-5080. Fax: (212) 448-5159. E-mail: cmayer{at}adarc.org.

§ Present address: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3080, Australia.

{dagger} C. Cheng-Mayer and P. N. Monk contributed equally to this work.

Journal of Virology, July 2006, p. 6487-6496, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02539-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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