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The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression

Nature Immunology volume 14, pages 1256–1265 (2013)Cite this article

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Abstract

The humoral immune response after acute infection with HIV-1 is delayed and ineffective. The HIV-1 envelope protein gp120 binds to and signals through integrin α4β7 on T cells. We found that gp120 also bound to and signaled through α4β7 on naive B cells, which resulted in an abortive proliferative response. In primary B cells, signaling by gp120 through α4β7 resulted in increased expression of the immunosuppressive cytokine TGF-β1 and FcRL4, an inhibitory receptor expressed on B cells. Coculture of B cells with HIV-1-infected autologous CD4+ T cells also increased the expression of FcRL4 by B cells. Our findings indicated that in addition to mediating chronic activation of the immune system, viral proteins contributed directly to HIV-1-associated B cell dysfunction. Our studies identify a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response.

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Figure 1: MAdCAM-1 and gp120 bind to α4β7 in a cation-dependent manner.
Figure 2: An α4β7-reactive gp120 inhibits B cell proliferation induced by α-IgM and CpG.
Figure 3: gp120 proteins with different affinity for α4β7 affect the gene expression of freshly isolated human B cells.
Figure 4: gp120 proteins with different affinity for α4β7 affect the gene expression of B cells stimulated with anti-IgM and CpG.
Figure 5: The induction of CD80 expression by stimulation with anti-IgM and CpG is reduced in presence of an α4β7-reactive gp120.
Figure 6: FcRL4 expression induced by stimulation with anti-IgM and CpG is increased and prolonged in presence of α4β7-reactive gp120.
Figure 7: gp120 induces FcRL4 via induction of TGF-β1.
Figure 8: Suppression of the T cell–dependent stimulation of B cells by α4β7-reactive gp120.

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Acknowledgements

We thank C. Derdeyn for HIV sequence information; A. Introini for suggestions; and J. Weddle and A. Weddle for assistance with figure preparation. Supported by the Intramural Research Program of the US National Institutes of Health (National Institute of Allergy and Infectious Diseases).

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  1. Claudia Cicala and Anthony S Fauci: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Katija Jelicic, Raffaello Cimbro, Fatima Nawaz, Massimiliano Pascuccio, Donald Van Ryk, Catherine Schwing, Joseph Hiatt, Noreen Okwara, Danlan Wei, Gregg Roby, II Young Hwang, John H Kehrl, James Arthos, Claudia Cicala & Anthony S Fauci

  2. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Raffaello Cimbro, Xin Zheng, Jun Yang & Richard A Lempicki

  3. New York University School of Medicine, Sackler Institute of Graduate Biomedical Sciences, New York, New York, USA

    Fatima Nawaz

  4. Laboratory of Immunopathogenesis and Bioinformatics, Science Applications International Corporation, Frederick, Maryland, USA

    Da Wei Huang

  5. Department of Internal Medicine, Faculty of Medicine, University of Messina, Messina, Italy

    Antonio David

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Contributions

K.J. did most of the experiments, analyzed the results and participated in manuscript preparation; R.C. contributed to flow cytometry and participated in manuscript preparation; F.N. did biological experiments, including gp120 binding; D.W.H. did bioinformatics analyses and contributed to the interpretation of microarray data; X.Z. did oligonucleotide microarray analysis and bioinformatics analyses; J.Y. did quantitative PCR experiment; R.A.L. did bioinformatics analyses; M.P., D.V.R. and C.S. produced and analyzed recombinant gp120; J.H. and N.O. did biological experiments; D.W. did experiments, including enzyme-linked immunosorbent assays; G.R. recruited blood donors; A.D. provided technical and intellectual contributions; I.Y.H. did experiments and provided technical contributions for CFSE experiments; J.H.K. contributed to analysis and to writing of the manuscript; J.A. contributed to study design and analysis and writing of the manuscript; C.C. conceived of and designed the study and interpreted data, supervised the study and composed the manuscript; A.S.F. supervised the study and contributed to writing the manuscript; and all authors reviewed the manuscript.

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Correspondence to Claudia Cicala.

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Integrated supplementary information

Supplementary Figure 1 Phenotype of stimulated human peripheral blood B cells in presence or not of HIV-1 gp120.

Surface expression of B cell markers, gated on freshly isolated B cells from PBMCs. a) Flow cytometry histograms show B cells at day 0 (black) versus α -IgM + CpG stimulated B cells at day 4 (red). b) B cells at day 0 (black) versus α -IgM + CpG + R66M gp120 stimulated B cells at day 4 (blue).

Supplementary Figure 2 Stimulation of memory B cells is affected by an α4β7 -reactive gp120.

a) % β7 expression on CD27- and CD27+ B cells p=0.0017 (Wilcoxon matched-pairs signed rank test) (n=13). Histograms of two representative donors to show the variability in β7 expression on CD27+ B cells. b) FACS analysis of CD80 surface expression induced by either a TI or a TD stimulation for 96h, in the presence or absence of an α4β7-reactive gp120 (R66M). Values reported are average % reactivity for five donors normalized to CD80 expression at 96h upon B cell stimulation (100%), p<0.0001 (two way ANOVA) (error bars, s.e.m ) (n=5). c) FACS analysis of CD86 surface expression. Values reported are average % reactivity for five donors normalized to CD86 expression at 96h upon B cell stimulation (100%) in the conditions described in panel b. d) FACS analysis of FcRL4 surface expression. Values reported are average % reactivity for five donors normalized to FcRL4 expression at 96h upon B cell stimulation (100%) in the conditions described in panel b. e) CFSE assay of TI stimulation of B cell proliferation (1st panel), in the presence of: an α4β7-reactive gp120 (2nd panel), an α4β7-reactive gp120 and an anti-TGF-β1 mAb (3rd panel), soluble TGF-β1 (4th panel), and soluble TGF-β1 plus an anti-TGF-β1 mAb (5th panel) of a representative donor. Cells were cultured for 96h. f) Division Index (FlowJo) for experiments described in panel e, indicating the average number of cell divisions, p<0.001 (two-way ANOVA) (n=5). Treatments are listed below the x-axis. g) CFSE assay of one representative donor as described in panel e but employing a TD inductive signal to induce proliferation of memory B cells. h) Division Index (FlowJo) for experiment in panel g of five donors indicating the average number of cell divisions, (NS) (two-way ANOVA) (n=5).

Source data

Supplementary Figure 3 Purification of recombinant gp120s.

Recombinant gp120s produced by transient transfection of non-adherent CHO-s cells were captured over a GNA lectin column and eluted with tris-glycine pH 3. Eluents were subjected to preparative size–exclusion over a superdex 200 10/60 column. Following concentration proteins were extracted twice with triton-X114 to remove trace endotoxin. Analytic size exclusion using a superdex 200 10/40 column (flow –rate 0.5 ml/min) was used to verify the purity of each preparation, which typically exceed 90%. A representative preparation of the pre- and post-size exclusion protein is shown.

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Jelicic, K., Cimbro, R., Nawaz, F. et al. The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression. Nat Immunol 14, 1256–1265 (2013). https://doi.org/10.1038/ni.2746

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