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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2802-2811.
Prepublished online as a Blood First Edition Paper on December 9, 2004; DOI 10.1182/blood-2004-06-2212.
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Submitted June 14, 2004
Accepted November 17, 2004
Cell surface-associated Tat modulates HIV-1 infection and spreading through a specific interaction with gp120 viral envelope protein
Serena Marchio*, Massimo Alfano, Luca Primo, Daniela Gramaglia, Luca Butini, Luisa Gennero, Enrico De Vivo, Wadih Arap, Mauro Giacca, Renata Pasqualini, and Federico Bussolino
Division of Molecular Angiogenesis, University of Turin Medical School, Institute for Cancer Research and Treatment, Candiolo, Italy; BioIndustry Park, Creabilis Therapeutics, Colleretto Giacosa, Italy
AIDS Immunopathogenesis Unit, Department of Immunology and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
Division of Molecular Angiogenesis, University of Turin Medical School, Institute for Cancer Research and Treatment, Candiolo, Italy
Division of Molecular Oncology, Department of Oncological Sciences, University of Turin Medical School, Institute for Cancer Research and Treatment, Candiolo, Italy
Service of Clinical Immunology, Department of Internal Medicine, Marche Polytechnic University School of Medicine and Ancona General Hospital, Ancona, Italy
Division of Infectious Diseases, Amedeo di Savoia Hospital, Turin, Italy
Service for Drug Addictions, A.S.L. 3, Turin, Italy
The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Molecular Medicine Laboratory, International Center for Genetic Engineering and Biotechnology, Trieste, Italy
* Corresponding author; email: serena.marchio{at}ircc.it.
Human Immunodeficiency Virus-1 (HIV-1) Tat, a nuclear transactivator of viral gene expression, has the unusual property of being released by infected cells. Recent studies suggest that extracellular Tat is partially sequestered by heparan sulfate proteoglycans. As a consequence, Tat is concentrated on the cell surface, and protected from proteolytic degradation, thus remaining in a biologically active form. We show that Tat binds the surfaces of both HIV-1-infected and surrounding, uninfected cells. We provide evidence for a specific interaction between Tat and the HIV-1 gp120 envelope protein, which enhances virus attachment and entry into cells. We map the interacting sites of both Tat and gp120, and show that synthetic peptides mimicking the gp120 site inhibit HIV-1 infection. Our data demonstrate that membrane-associated Tat is a novel modulator of virus entry, and suggest that the Tat/gp120 interaction represents a critical step in HIV-1 spreading during the course of infection.
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