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 language | English (US) |
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Pages (from-to) | 63-76 |
Number of pages | 14 |
Journal | Cell Host and Microbe |
Volume | 4 |
Issue number | 1 |
DOIs | |
State | Published - Jul 17 2008 |
Externally published | Yes |
Keywords
- CELLIMMUNO
- MICROBIO
- MOLIMMUNO
ASJC Scopus subject areas
- Immunology and Microbiology(all)
- Cancer Research
- Molecular Biology