Evidence for a pathogenic determinant in HIV-1 Nef involved in B cell dysfunction in HIV/AIDS.
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.
Swingler
Simon
S
University of Massachusetts Medical School, Program in Molecular Medicine, 373 Plantation Street, Worcester, MA 01605, USA. simon.swingler@umassmed.edu <simon.swingler@umassmed.edu>
Zhou
Jin
J
Swingler
Catherine
C
Dauphin
Ann
A
Greenough
Thomas
T
Jolicoeur
Paul
P
Stevenson
Mario
M
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D005293:Ferritins / Q000097:blood / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D006942:Hypergammaglobulinemia; D008213:Lymphocyte Activation; D008264:Macrophages / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D013223:Statistics as Topic; D019562:Viral Load; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000502:physiology*
D016328:NF-kappa B; D037521:Virulence Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D005293:Ferritins