title: HIV-1 tat promotes integrin-mediated HIV transmission to dendritic cells by binding Env spikes and competes neutralization by anti-HIV antibodies.
abstract: Use of Env in HIV vaccine development has been disappointing. Here we show that, in the presence of a biologically active Tat subunit vaccine, a trimeric Env protein prevents in monkeys virus spread from the portal of entry to regional lymph nodes. This appears to be due to specific interactions between Tat and Env spikes that form a novel virus entry complex favoring R5 or X4 virus entry and productive infection of dendritic cells (DCs) via an integrin-mediated pathway. These Tat effects do not require Tat-transactivation activity and are blocked by anti-integrin antibodies (Abs). Productive DC infection promoted by Tat is associated with a highly efficient virus transmission to T cells. In the Tat/Env complex the cysteine-rich region of Tat engages the Env V3 loop, whereas the Tat RGD sequence remains free and directs the virus to integrins present on DCs. V2 loop deletion, which unshields the CCR5 binding region of Env, increases Tat/Env complex stability. Of note, binding of Tat to Env abolishes neutralization of Env entry or infection of DCs by anti-HIV sera lacking anti-Tat Abs, which are seldom present in natural infection. This is reversed, and neutralization further enhanced, by HIV sera containing anti-Tat Abs such as those from asymptomatic or Tat-vaccinated patients, or by sera from the Tat/Env vaccinated monkeys. Thus, both anti-Tat and anti-Env Abs are required for efficient HIV neutralization. These data suggest that the Tat/Env interaction increases HIV acquisition and spreading, as a mechanism evolved by the virus to escape anti-Env neutralizing Abs. This may explain the low effectiveness of Env-based vaccines, which are also unlikely to elicit Abs against new Env epitopes exposed by the Tat/Env interaction. As Tat also binds Envs from different clades, new vaccine strategies should exploit the Tat/Env interaction for both preventative and therapeutic interventions.
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Monini
authors.forename: Aurelio
authors.initials: A
authors.lastname: Cafaro
authors.forename: Indresh K
authors.initials: IK
authors.lastname: Srivastava
authors.forename: Sonia
authors.initials: S
authors.lastname: Moretti
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Sharma
authors.forename: Claudia
authors.initials: C
authors.lastname: Andreini
authors.forename: Chiara
authors.initials: C
authors.lastname: Chiozzini
authors.forename: Flavia
authors.initials: F
authors.lastname: Ferrantelli
authors.forename: Maria R Pavone
authors.initials: MR
authors.lastname: Cossut
authors.forename: Antonella
authors.initials: A
authors.lastname: Tripiciano
authors.forename: Filomena
authors.initials: F
authors.lastname: Nappi
authors.forename: Olimpia
authors.initials: O
authors.lastname: Longo
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellino
authors.forename: Orietta
authors.initials: O
authors.lastname: Picconi
authors.forename: Emanuele
authors.initials: E
authors.lastname: Fanales-Belasio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Borsetti
authors.forename: Elena
authors.initials: E
authors.lastname: Toschi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Schiavoni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bacigalupo
authors.forename: Elaine
authors.initials: E
authors.lastname: Kan
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sernicola
authors.forename: Maria T
authors.initials: MT
authors.lastname: Maggiorella
authors.forename: Katy
authors.initials: K
authors.lastname: Montin
authors.forename: Marco
authors.initials: M
authors.lastname: Porcu
authors.forename: Patrizia
authors.initials: P
authors.lastname: Leone
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Leone
authors.forename: Barbara
authors.initials: B
authors.lastname: Collacchi
authors.forename: Clelia
authors.initials: C
authors.lastname: Palladino
authors.forename: Barbara
authors.initials: B
authors.lastname: Ridolfi
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.forename: Iole
authors.initials: I
authors.lastname: Macchia
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Ulmer
authors.forename: Stefano
authors.initials: S
authors.lastname: Buttò
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sgadari
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Maurizio P M
authors.initials: MP
authors.lastname: Federico
authors.forename: Fausto
authors.initials: F
authors.lastname: Titti
authors.forename: Lucia
authors.initials: L
authors.lastname: Banci
authors.forename: Franco
authors.initials: F
authors.lastname: Dallocchio
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ensoli
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnett
authors.forename: Enrico
authors.initials: E
authors.lastname: Garaci
authors.forename: Barbara
authors.initials: B
authors.lastname: Ensoli
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology*; D015483:HIV Antibodies / Q000276:immunology / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D062105:Molecular Docking Simulation; D009500:Neutralization Tests; D009842:Oligopeptides / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000276:immunology; D053586:Virus Internalization; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D016023:Integrins; D009842:Oligopeptides; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D058425:Vaccines, Virus-Like Particle; D054299:env Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus; C047981:arginyl-glycyl-aspartic acid