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

Nature Immunology volume 7, pages 302–310 (2006)Cite this article

A Corrigendum to this article was published on 20 September 2016

Abstract

Immunoglobulin class switching from immunoglobulin M (IgM) to IgG and IgA is central to immunity against viruses and requires the activation of B cells by T cells via CD154 (CD40 ligand) and cytokines. These molecules limit their signaling activity in immune cells by turning on negative feedback proteins, including IκB and SOCS. We show here that negative factor (Nef) protein, an immunosuppressive human immunodeficiency virus 1 protein expressed and released by infected cells, penetrates B cells both in vivo and in vitro. Nef suppressed immunoglobulin class-switch DNA recombination by inducing IκBα and SOCS proteins, which blocked CD154 and cytokine signaling via NF-κB and STAT transcription factors. Thus, human immunodeficiency virus 1 may evade protective T cell–dependent IgG and IgA responses by 'hijacking' physiological feedback inhibitors in B cells via Nef.

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Figure 1: B cells accumulate Nef in vivo.
Figure 2: Nef penetrates in B cells in vitro and inhibits induction of CSR by CD154 and IL-4.
Figure 3: Nef inhibits the production of IgG, IgA and IgE in B cells exposed to CD154 and IL-4.
Figure 4: Nef does not downregulate CD40, IL-4 and IL-10 receptors on B cells.
Figure 5: Nef inhibits CD154 signaling through NF-κB in B cells.
Figure 6: Nef inhibits cytokine signaling through the Jak-STAT pathway in B cells.
Figure 7: Nef induces IκBα, SOCS1 and SOCS3 in B cells.

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Acknowledgements

We thank J.P. Moore and K.A. Smith (Weill Medical College of Cornell University, New York) for discussions. Supported by the National Institutes of Health (AI057530 and AI057653 to A.C.).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Xugang Qiao, Bing He, April Chiu, Daniel M Knowles, Amy Chadburn & Andrea Cerutti

  2. Graduate Program of Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Andrea Cerutti

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Supplementary information

Supplementary Fig. 1

p17 does not penetrate in B cells in vivo. (PDF 823 kb)

Supplementary Fig. 2

Low concentrations of Nef are sufficient to enter B cells and inhibit TD CSR and Ig secretion. (PDF 101 kb)

Supplementary Fig. 3

Low concentrations of Nef are sufficient to inhibit CD40 signaling through NF-κB and IL-4 signaling through STAT6 in B cells. (PDF 181 kb)

Supplementary Fig. 4

Nef suppresses TD CSR and antibody production in bystander B cells. (PDF 146 kb)

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Qiao, X., He, B., Chiu, A. et al. Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol 7, 302–310 (2006). https://doi.org/10.1038/ni1302

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