Abstract
The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is a vaccine immunogen that can signal via several cell surface receptors. To investigate whether receptor biology could influence immune responses to gp120, we studied its interaction with human, monocyte-derived dendritic cells (MDDCs) in vitro. Gp120 from the HIV-1 strain JR-FL induced IL-10 expression in MDDCs from 62% of donors, via a mannose C-type lectin receptor(s) (MCLR). Gp120 from the strain LAI was also an IL-10 inducer, but gp120 from the strain KNH1144 was not. The mannose-binding protein cyanovirin-N, the 2G12 mAb to a mannose-dependent gp120 epitope, and MCLR-specific mAbs inhibited IL-10 expression, as did enzymatic removal of gp120 mannose moieties, whereas inhibitors of signaling via CD4, CCR5, or CXCR4 were ineffective. Gp120-stimulated IL-10 production correlated with DC-SIGN expression on the cells, and involved the ERK signaling pathway. Gp120-treated MDDCs also responded poorly to maturation stimuli by up-regulating activation markers inefficiently and stimulating allogeneic T cell proliferation only weakly. These adverse reactions to gp120 were MCLR-dependent but independent of IL-10 production. Since such mechanisms might suppress immune responses to Env-containing vaccines, demannosylation may be a way to improve the immunogenicity of gp120 or gp140 proteins.
Highlights
One approach to a vaccine against human immunodeficiency virus type 1 (HIV-1) is the use of the viral envelope glycoproteins (Env) as immunogens to induce neutralizing antibodies (NAbs) [1,2,3]
These various effects of gp120 are caused by its binding to cell surface receptors of the mannose Ctype lectin receptor family, including one called dendritic cell (DC)-SIGN
HIV-1 gp120 Induces monocyte-derived dendritic cell (MDDC) to Produce IL-10 We investigated how gp120 affected MDDC maturation and cytokine secretion, and MDDC-T cell interactions in view of the key role dendritic cells (DCs) play in antigen capture, processing, and presentation
Summary
One approach to a vaccine against HIV-1 is the use of the viral envelope glycoproteins (Env) as immunogens to induce neutralizing antibodies (NAbs) [1,2,3]. Different configurations of Env glycoproteins have been studied as vaccine antigens, initially the surface glycoprotein gp120; more recently, soluble oligomeric gp140 proteins based broadly on the native gp120-gp complex [1,2,3]. Irrespective of how HIV-1 Env glycoproteins have been presented and in whatever configuration, the induction of broadly active NAbs has proven problematic [1]. One generally accepted problem is the evolution of the native Env complex into a configuration that limits the exposure of the few neutralization sites that are present. We focus on what we consider to be another factor hindering NAb induction: the limited immunogenicity of HIV-1 Env proteins in general
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