HIV-1 tat promotes integrin-mediated HIV transmission to dendritic cells by binding Env spikes and competes neutralization by anti-HIV antibodies.

Paolo Monini,Clelia Palladino,Marco Porcu,Barbara Ensoli,Victoria A Sharma,Flavia Ferrantelli,Patrizia Leone,Aurelio Cafaro,Katy Montin,Indresh K Srivastava,Cecilia Sgadari,Mauro Magnani,Elaine Kan,Pasqualina Leone,Orietta Picconi,Barbara Collacchi,Filomena Nappi,Fabrizio Ensoli,Ilaria Bacigalupo,Olimpia Longo,Mario Falchi,Elena Toschi,Lucia Banci,Enrico Garaci,Stefania Bellino,Stefano Buttò,Franco Dallocchio,Claudia Andreini,Fausto Titti,Iole Macchia,Ilaria Schiavoni,Antonella Tripiciano,Jeffrey B Ulmer,Sonia Moretti,Chiara Chiozzini,Barbara Ridolfi,Emanuele Fanales-Belasio,Leonardo Sernicola,Rino Rappuoli,Susan W Barnett,Maria Teresa Maggiorella ,Maria Rosaria Pavone Cossut ,Maurizio Federico ,Alessândra Borsetti

doi:10.1371/journal.pone.0048781

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.

Highlights

HIV-1 preventative vaccines based on the HIV Env antigen have either failed or shown marginal protection [1,2,3], indicating that Env is not sufficient to protect against infection and that innovative approaches are needed
Extracellular Tat is mostly bound to heparan sulfate proteoglycans (HSPG) of the extracellular matrix (ECM) [16,17], and engages the arginine-glycine-aspartic acid (RGD)binding integrins avb3, a5b1 and avb5 on activated endothelial cells and co-stains with these integrins in tissues from infected individuals [17,22,23,24,25,26,27,28]. These integrins are highly expressed by dendritic cells (DCs) and macrophages, which are known: I) to be a main target of HIV at the portal of entry, II) to favor the establishment and spreading of the infection, and III) to become viral reservoirs in chronic infection
We found that mucosal vaccination with the combination of Tat and Env proteins protected non-human primates against an intrarectal challenge with a high dose of an R5-SHIV

Summary

Introduction

HIV-1 preventative vaccines based on the HIV Env antigen have either failed or shown marginal protection [1,2,3], indicating that Env is not sufficient to protect against infection and that innovative approaches are needed. Extracellular Tat is mostly bound to heparan sulfate proteoglycans (HSPG) of the extracellular matrix (ECM) [16,17], and engages the arginine-glycine-aspartic acid (RGD)binding integrins avb, a5b1 and avb on activated endothelial cells and co-stains with these integrins in tissues from infected individuals [17,22,23,24,25,26,27,28] These integrins are highly expressed by DCs and macrophages, which are known: I) to be a main target of HIV at the portal of entry, II) to favor the establishment and spreading of the infection, and III) to become viral reservoirs in chronic infection. Extracellular adherent Tat can efficiently increase virus transmission to T cells [33]

Methods

Results

Conclusion