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

PLoS One. 2012;7(11):e48781. doi: 10.1371/journal.pone.0048781. Epub 2012 Nov 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / administration & dosage
  • AIDS Vaccines / immunology
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / metabolism
  • Binding Sites
  • Dendritic Cells / immunology
  • Dendritic Cells / virology*
  • HIV Antibodies / immunology
  • HIV Antibodies / metabolism*
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism
  • HIV Infections / immunology
  • HIV Infections / prevention & control
  • HIV Infections / transmission
  • HIV Infections / virology
  • HIV-1 / immunology
  • HIV-1 / metabolism*
  • Humans
  • Integrins / immunology
  • Integrins / metabolism*
  • Macaca fascicularis
  • Male
  • Molecular Docking Simulation
  • Neutralization Tests
  • Oligopeptides / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs / immunology
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / metabolism
  • Recombinant Proteins / immunology
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology
  • Vaccines, Virus-Like Particle / administration & dosage
  • Vaccines, Virus-Like Particle / immunology
  • Virus Internalization
  • Virus Replication
  • env Gene Products, Human Immunodeficiency Virus / chemistry
  • env Gene Products, Human Immunodeficiency Virus / immunology
  • env Gene Products, Human Immunodeficiency Virus / metabolism*
  • tat Gene Products, Human Immunodeficiency Virus / chemistry
  • tat Gene Products, Human Immunodeficiency Virus / immunology
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Integrins
  • Oligopeptides
  • Receptors, CCR5
  • Receptors, CXCR4
  • Recombinant Proteins
  • Vaccines, Virus-Like Particle
  • env Gene Products, Human Immunodeficiency Virus
  • tat Gene Products, Human Immunodeficiency Virus
  • arginyl-glycyl-aspartic acid

Grants and funding

This work was supported by grants from EC Commission under the VI Framework Programme of Research and Technological Development (2002 - 2006), project number LSHP-CT-2004-503487, AIDS Vaccine Integrated Project (“AVIP”) and from the Very Innovative AIDS Vaccine Project (“VIAV”, European Commission), from the Italian National AIDS Program, ISS, Italian Ministry of Health to the National AIDS Center, from the Italian Concerted Action for the Development of a Vaccine against HIV/Tat (ICAV), Italian Ministry of Health and from the “Joint Program ISS/Novartis (Chiron) for the development of a combined vaccine against HIV/AIDS” to BE and RR, from the special project on the Development of a Vaccine against HIV/Tat, Italian Ministry of Health to BE, and by National Institutes of Health grants to S.W.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.