The B-oligomer of pertussis toxin deactivates CC chemokine receptor 5 and blocks entry of M-tropic HIV-1 strains

Massimo Alfano, Helena Schmidtmayerova, Carol Ann Amelia, Tatiana Pushkarsky, Michael Bukrinsky

Research output: Contribution to journalArticle

Abstract

Infection of target cells by HIV-1 requires initial binding interactions between the viral envelope glycoprotein gp120, the cell surface protein CD4, and one of the members of the seven-transmembrane G protein-coupled chemokine receptor family. Most primary isolates (R5 strains) use chemokine receptor CCR 5, but some primary syncytium-inducing, as well as T cell line-adapted, strains (X4 strains) use the CXCR4 receptor. Signaling from both CCR5 and CXCR4 is mediated by pertussis toxin (PTX)-sensitive G1 proteins and is not required for HIV-1 entry. Here, we show that the PTX holotoxin as well as its banding subunit, B-oligomer, which lacks G1-inhibitory activity, blocked entry of R5 but not X4 strains into primary T lymphocytes. Interestingly, B- oligomer inhabited virus production by peripheral blood mononuclear cell cultures infected with either R5 or X4 strains, indicating that it can affect HIV-1 replication at both entry and post-entry levels. T cells treated with B-oligomer did not initiate signal transduction in response to macrophage inflammatory protean (MIP)-1β or RANTES (regulated upon activation, normal T cell expressed and secreted); however, cell surface expression of CCR5 and banding of MIP-1β or HIV-1 to such cells were not impaired. The inhibitory effect of B-oligomer on signaling from CCR5 and on entry of R5 HIV-1 strains was reversed by protean kinase C (PKC) inhibitors, indicating that B-oligomer activity is mediated by signaling events that involve PKC. B-oligomer also blocked cocapping of CCR5 and CD4 induced by R5 HIV-1 an primary T cells, but did not affect cocapping of CXCR4 and CD4 after inoculation of the cultures with X4 HIV-1. These results suggest that the B-oligomer of PTX cross- deactivates CCR5 to impair its function as a coreceptor for HIV-1.

Original languageEnglish
Pages (from-to)597-605
Number of pages9
JournalJournal of Experimental Medicine
Volume190
Issue number5
DOIs
Publication statusPublished - Sep 6 1999

Keywords

  • CCR5
  • G protein
  • Receptor capping
  • Receptor desensitization
  • Signal transduction

ASJC Scopus subject areas

  • Immunology

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