Abstract
B lymphocyte hyperactivation and hypergammaglobulinemia are pathogenic manifestations of HIV-1 infection. Here we provide evidence that these B cell defects are driven by factors produced by HIV-1 infected macrophages and that Nef is necessary for this activity.
In vitro
, HIV-1 infected macrophages or macrophages expressing Nef promoted B cell activation and differentiation to immunoglobulin-secreting cells. Activation of NF-κB by Nef induced secretion of the acute-phase reactant ferritin and ferritin was necessary and sufficient for these B cell effects. The extent of hypergammaglobulinemia in HIV-1 infected individuals correlated directly with plasma ferritin levels and with viral load. We further demonstrate that induction of ferritin and hypergammaglobulinemia could be recapitulated when Nef was specifically expressed in macrophages and T cells of transgenic mice. Collectively, these results reveal the presence of a pathogenic determinant within the Nef protein of HIV-1 which governs B cell defects in HIV-1 infection.
