MAdCAM costimulation through Integrin-α4β7 promotes HIV replication

Fatima Nawaz, Livia R. Goes, Jocelyn C. Ray, Ronke Olowojesiku, Alia Sajani, Aftab A. Ansari, Ian Perrone, Joseph Hiatt, Donald Van Ryk, Danlan Wei, Mia Waliszewski, Marcelo A. Soares, Katija Jelicic, Mark Connors, Stephen A. Migueles, Elena Martinelli, Francois Villinger, Claudia Cicala, Anthony S. Fauci, James Arthos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1342-1351
Number of pages10
JournalMucosal Immunology
Volume11
Issue number5
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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