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-kappaB 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.
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Authors | Simon Swingler, Jin Zhou, Catherine Swingler, Ann Dauphin, Thomas Greenough, Paul Jolicoeur, Mario Stevenson |
Journal | Cell host & microbe
(Cell Host Microbe)
Vol. 4
Issue 1
Pg. 63-76
(Jul 17 2008)
ISSN: 1934-6069 [Electronic] United States |
PMID | 18621011
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- NF-kappa B
- Virulence Factors
- nef Gene Products, Human Immunodeficiency Virus
- nef protein, Human immunodeficiency virus 1
- Ferritins
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Topics |
- Animals
- B-Lymphocytes
(immunology)
- Ferritins
(blood, metabolism)
- HIV-1
(genetics, pathogenicity)
- Humans
- Hypergammaglobulinemia
- Lymphocyte Activation
- Macrophages
(virology)
- Mice
- Mice, Transgenic
- NF-kappa B
(metabolism)
- Statistics as Topic
- Viral Load
- Virulence Factors
(genetics, physiology)
- nef Gene Products, Human Immunodeficiency Virus
(genetics, physiology)
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