MAdCAM costimulation through Integrin-α 4 β 7 promotes HIV replication

Mucosal Immunol. 2018 Sep;11(5):1342-1351. doi: 10.1038/s41385-018-0044-1. Epub 2018 Jun 6.

Abstract

Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4β7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with α4β7. Such costimulation promotes high levels of HIV replication. An anti-α4β7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α4β7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-α4β7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α4β7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Endothelial Cells / metabolism
  • Endothelial Cells / virology
  • Female
  • HIV / drug effects
  • HIV / physiology*
  • HIV Infections / drug therapy
  • HIV Infections / metabolism*
  • Humans
  • Immunologic Memory / drug effects
  • Integrins / metabolism*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / virology
  • Lymphoid Tissue / metabolism
  • Lymphoid Tissue / virology
  • Macaca mulatta
  • Protein Interaction Domains and Motifs
  • Receptors, CCR5 / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tretinoin / metabolism
  • Up-Regulation / drug effects
  • Virus Replication / drug effects
  • Virus Replication / physiology*

Substances

  • Antibodies, Monoclonal, Humanized
  • Integrins
  • Receptors, CCR5
  • integrin alpha4beta7
  • Tretinoin
  • vedolizumab