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Plasmacytoid dendritic cells mediate synergistic effects of HIV and
lipopolysaccharide on CD27+ IgD- memory B cell apoptosis
#MMPMID25056888
Zhang L
; Luo Z
; Sieg SF
; Funderburg NT
; Yu X
; Fu P
; Wu H
; Jiao Y
; Gao Y
; Greenspan NS
; Harding CV
; Kilby JM
; Li Z
; Lederman MM
; Jiang W
J Virol
2014[Oct]; 88
(19
): 11430-41
PMID25056888
show ga
The effects of heightened microbial translocation on B cells during HIV infection
are unknown. We examined the in vitro effects of HIV and lipopolysaccharide (LPS)
on apoptosis of CD27+ IgD- memory B (mB) cells from healthy controls. In vivo
analysis was conducted on a cohort of 82 HIV+ donors and 60 healthy controls. In
vitro exposure of peripheral blood mononuclear cells (PBMCs) to LPS and HIV led
to mB cell death via the Fas/Fas ligand (FasL) pathway. Plasmacytoid dendritic
cells (pDCs) produced FasL in response to HIV via binding to CD4 and chemokine
coreceptors. HIV and LPS increased Fas expression on mB cells in PBMCs, which was
dependent on the presence of pDCs and monocytes. Furthermore, mB cells purified
from PBMCs and pretreated with both HIV and LPS were more sensitive to apoptosis
when cocultured with HIV-treated pDCs. Blocking the interferon receptor (IFNR)
prevented HIV-stimulated FasL production in pDCs, HIV-plus-LPS-induced Fas
expression, and apoptosis of mB cells. In vivo or ex vivo, HIV+ donors have
higher levels of plasma LPS, Fas expression on mB cells, and mB cell apoptosis
than controls. Correspondingly, in HIV+ donors, but not in controls, a positive
correlation was found between plasma FasL and HIV RNA levels and between Fas
expression on mB cells and plasma LPS levels. This work reveals a novel mechanism
of mB cell apoptosis mediated by LPS and HIV through the Fas/FasL pathway, with
key involvement of pDCs and type I IFN, suggesting a role for microbial
translocation in HIV pathogenesis. IMPORTANCE: This study demonstrates that
lipopolysaccharide (LPS) and type I interferon (IFN) play an important role in
memory B cell apoptosis in HIV infection. It reveals a previously unrecognized
role of microbial translocation in HIV pathogenesis.
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