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 |
|---|---|
| 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 |
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Keywords
- CELLIMMUNO
- MICROBIO
- MOLIMMUNO
ASJC Scopus subject areas
- Immunology and Microbiology(all)
- Cancer Research
- Molecular Biology
Cite this
Evidence for a Pathogenic Determinant in HIV-1 Nef Involved in B Cell Dysfunction in HIV/AIDS. / Swingler, Simon; Zhou, Jin; Swingler, Catherine; Dauphin, Ann; Greenough, Thomas; Jolicoeur, Paul; Stevenson, Mario.
In: Cell Host and Microbe, Vol. 4, No. 1, 17.07.2008, p. 63-76.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Evidence for a Pathogenic Determinant in HIV-1 Nef Involved in B Cell Dysfunction in HIV/AIDS
AU - Swingler, Simon
AU - Zhou, Jin
AU - Swingler, Catherine
AU - Dauphin, Ann
AU - Greenough, Thomas
AU - Jolicoeur, Paul
AU - Stevenson, Mario
PY - 2008/7/17
Y1 - 2008/7/17
N2 - 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.
AB - 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.
KW - CELLIMMUNO
KW - MICROBIO
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=46949095793&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=46949095793&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2008.05.015
DO - 10.1016/j.chom.2008.05.015
M3 - Article
C2 - 18621011
AN - SCOPUS:46949095793
VL - 4
SP - 63
EP - 76
JO - Cell Host and Microbe
JF - Cell Host and Microbe
SN - 1931-3128
IS - 1
ER -