Evidence for a Pathogenic Determinant in HIV-1 Nef Involved in B Cell Dysfunction in HIV/AIDS

Simon Swingler, Jin Zhou, Catherine Swingler, Ann Dauphin, Thomas Greenough, Paul Jolicoeur, Mario Stevenson

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

B lymphocyte hyperactivation and elevated immunoglobulin levels (hypergammaglobulinemia) are pathogenic manifestations of HIV-1 infection. Here we provide evidence that these hallmarks are caused by a soluble factor whose production by infected macrophages is induced by the HIV-1 Nef protein. In vitro, HIV-1-infected macrophages or macrophages expressing Nef promoted B cell activation and differentiation to immunoglobulin-secreting cells. Nef-mediated activation of NF-κB in macrophages induced secretion of the acute-phase protein ferritin, and ferritin was necessary and sufficient for the observed Nef-dependent B cell changes. The extent of hypergammaglobulinemia in HIV-1-infected individuals correlated directly with plasma ferritin levels and with viral load. Furthermore, the induction of ferritin production and hypergammaglobulinemia was recapitulated when Nef was specifically expressed in macrophages and T cells of transgenic mice. Collectively, these results indicate that the HIV-1 Nef protein carries a pathogenic determinant that governs B cell defects in HIV-1 infection.

Original languageEnglish (US)
Pages (from-to)63-76
Number of pages14
JournalCell Host and Microbe
Volume4
Issue number1
DOIs
StatePublished - Jul 17 2008

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Keywords

  • CELLIMMUNO
  • MICROBIO
  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Cancer Research
  • Molecular Biology

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