Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells

Nat. Immunol. 7: 302-310 (2006)

Speaker:徐英展                            Time: 2006/05/03 15:10~16:00

Commentator:陳舜華 老師                   Place: Room 601

Abstract:

In acquired immunodeficiency syndrome (AIDS), B cell defect with impaired IgG and IgA response is also important as well as T cell defect. Although HIV-1 promotes depletion of CD4⁺ T cells and degeneration of follicular dendritic cell, these mechanisms are not sufficient to explain humoral defects arising at an early stage, nor can they account for the intrinsically poor responsiveness of B cells to CD4⁺ T cell help¹. HIV-1 can not infect B cells, therefore, it must alter their function in an indirect way. In this paper, the authors found that negative factor (Nef) protein, an early HIV-1 protein which could be released into extracellular environment by HIV-1-infected cell, would penetrate B cells both in vivo and in vitro. After the entrance of Nef into B cells, Nef will inhibit the initiation of immunoglobulin heavy-chain class-switch recombination (CSR) by three mechanisms. First, Nef inhibits the signal transduction from CD40 receptor through NF-κB by attenuating CD40-mediated IκBα degradation and increasing IκBαsynthesis. Second, Nef dampens interleukin-4 (IL-4) signaling of STAT6 by decreasing IL-4 receptor –mediated Jak1 and Jak3 activation, thereby impairing phosphorylation and nuclear translocation of STAT6. Third, Nef inhibits IL-10 signaling through Jak1, STAT1 and STAT3, thereby preventing the differentiation of naïve B cells into antibody-secreting cells. In  conclusion, the induction of IκBαand SOCS by Nef impairs the CSR by inhibition of NF-κB and Jak-STAT signaling and HIV-1 may evade protective T cell-dependent IgG and IgA responses by hijacking physiological feedback inhibitors in B cells via Nef.

Reference:

1. Moir, S. et al. Perturbations in B cell responsiveness to CD4⁺ T cell help in HIV-infected individuals. Proc. Natl. Acad. Sci. USA 100, 6057-6062 (2003).