Cell surface-associated Tat modulates HIV-1 infection and spreading through a specific interaction with gp120 viral envelope protein.
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 glycoprotein 120 (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.
Marchiò
Serena
S
Division of Molecular Angiogenesis, Department of Oncological Sciences, University of Turin Medicine School, Institute for Cancer Research and Treatment, Sp 142, km 3.95-10060 Candiolo (TO) Italy. serena.marchio@ircc.it
Alfano
Massimo
M
Primo
Luca
L
Gramaglia
Daniela
D
Butini
Luca
L
Gennero
Luisa
L
De Vivo
Enrico
E
Arap
Wadih
W
Giacca
Mauro
M
Pasqualini
Renata
R
Bussolino
Federico
F
D015696:Gene Products, tat / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D018716:Molecular Mimicry; D009504:Neutrophils / Q000378:metabolism / Q000821:virology; D019151:Peptide Library; D011485:Protein Binding; D020298:U937 Cells; D014774:Virulence; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D008024:Ligands; D008565:Membrane Proteins; D019151:Peptide Library; D054322:tat Gene Products, Human Immunodeficiency Virus