The immunosuppressive domain of the transmembrane envelope protein gp41 of HIV-1 binds to human monocytes and B cells

Mühle, Michael; Kroniger, Tobias; Hoffmann, Kerstin; Denner, Joachim

doi:10.1007/s12026-015-8776-4

Cited by 5 publications

(6 citation statements)

References 37 publications

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“…The finding that the gp41 binds to monocytes and to a lesser extent to lymphocytes confirms recent data showing that homopolymers of peptides corresponding to the Isu domain of gp41 did bind predominantly to human classical and intermediate monocytes and B cells [22]. Similar to the previous investigations, an uptake via endocytosis or by the LPS (TLR4/CD14/MD2) receptor could be excluded through the experimental set-up: performing the incubation at 4°C and showing that the preparation did not contain LPS.…”

Section: Discussionsupporting

confidence: 86%

“…Next to this, it will be interesting to investigate gp41 binding on a larger cohort of PBMC donors to evaluate whether donor-dependent differences exist. Based on previous results obtained with the gp41 immunosuppressive peptide [22], this might be anticipated.…”

Section: Discussionmentioning

confidence: 82%

“…However, since synthetic peptides corresponding to the Isu domain were able to inhibit lymphocyte proliferation and to modulate cytokine release and gene expression [17, 30, 37] and were binding to PBMCs [21, 22], we suggest that glycosylation is not required for binding and immunosuppressive activities.…”

Section: Discussionmentioning

confidence: 99%

“…Using recombinant gp41 produced in bacteria, different binding proteins on the surface of immune human cells were found [19, 20]. Recently, using monomers or polymers of synthetic peptides corresponding to the Isu domain of HIV-1, binding proteins on human lymphocytes were allocated to individual PBMC sub-populations, mainly to monocytes and B-cells [21, 22]. …”

Section: Introductionmentioning

confidence: 99%

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Antigenic and immunosuppressive properties of a trimeric recombinant transmembrane envelope protein gp41 of HIV-1

et al. 2017

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The transmembrane envelope (TM) protein gp41 of the human immunodeficiency virus—1 (HIV-1) plays an important role during virus infection inducing the fusion of the viral and cellular membranes. In addition, there are indications that the TM protein plays a role in the immunopathogenesis leading to the acquired immunodeficiency syndrome (AIDS). Inactivated virus particles and recombinant gp41 have been reported to inhibit lymphocyte proliferation, as well as to alter cytokine release and gene expression. The same was shown for a peptide corresponding to a highly conserved domain of all retroviral TM proteins, the immunosuppressive domain. Due to its propensity to aggregate and to be expressed at low levels, studies comprising authentic gp41 produced in eukaryotic cells are extremely rare. Here we describe the production of a secreted, soluble recombinant gp41 in 293 cells. The antigen was purified to homogeneity and characterised thoroughly by various biochemical and immunological methods. It was shown that the protein was glycosylated and assembled into trimers. Binding studies by ELISA and surface plasmon resonance using conformation-specific monoclonal antibodies implied a six-helix bundle conformation. The low binding of broadly neutralising antibodies (bnAb) directed against the membrane proximal external region (MPER) suggested that this gp41 is probably not suited as vaccine to induce such bnAb. Purified gp41 bound to monocytes and to a lesser extent to lymphocytes and triggered the production of specific cytokines when added to normal peripheral blood mononuclear cells. In addition, gp41 expressed on target cells inhibited the antigen-specific response of murine CD8+ T cells by drastically impairing their IFNγ production. To our knowledge, this is the first comprehensive analysis of a gp41 produced in eukaryotic cells including its immunosuppressive properties. Our data provide another line of evidence that gp41 might be directly involved in HIV-1 immunopathogenesis through modulation of the cytokine release and active inhibition of immune responses.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antigenic and immunosuppressive properties of a trimeric recombinant transmembrane envelope protein gp41 of HIV-1

et al. 2017

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“…The mechanism how the ISU domain interacts with immune cells is still unclear. There are several reports showing binding of the TM proteins or synthetic peptides corresponding to the ISU domain to monocytes and B cells [ 64 – 68 ].…”

Section: Discussionmentioning

confidence: 99%

Absence of IL-10 production by human PBMCs co-cultivated with human cells expressing or secreting retroviral immunosuppressive domains

et al. 2018

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Immunosuppression by retroviruses including the human immunodeficiency virus—1 (HIV-1) is well known, however the mechanisms how retroviruses induce this immunosuppression is not fully investigated. It was shown that non-infectious retroviral particles as well as retroviral or recombinant retroviral transmembrane envelope (TM) proteins demonstrated immunosuppressive properties. The same was shown for peptides corresponding to a highly conserved domain in the TM protein. This domain is called immunosuppressive (ISU) domain and it induces modulation of the cytokine release of peripheral blood mononuclear cells (PBMCs) from healthy donors. In addition, it changes the gene expression of these cells. Common indications for the immunosuppressive activity were tumour growth in vivo and interleukin—10 (IL-10) release from human PBMCs in vitro. Single mutations in the ISU domain abrogated the immunosuppressive activity. In order to develop a new model system for the expression of the ISU domain and presentation to PBMCs which is not prone to possible endotoxin contaminations, two expression systems were developed. In the first system, designated pOUT, retroviral proteins containing the ISU domain were expressed and released into the cell culture medium, and in the second system, tANCHOR, the ISU domain was presented by a tetraspanin-anchored sequence on the cell surface of human cells. Both systems were exploited to express the wild-type (wt) ISU domains of HIV-1, of the porcine endogenous retrovirus (PERV) and of the murine leukaemia virus (MuLV) as well as to express mutants (mut) of these ISU domains. PERV is of special interest in the context of virus safety of xenotransplantation using pig organs. Expression of the TM proteins was demonstrated by confocal laser scanning microscopy, ELISA and Western blot analyses using specific antibodies. However, when cells expressing and releasing the ISU were co-incubated with human PBMCs, no increased production of IL-10 was observed when compared with the mutants. Similar results were obtained when the released TM proteins were concentrated by immunoprecipitation and added to PBMCs. We suggest that the absence of IL-10 induction can be explained by a low amount of protein, by the lack of a biologically active conformation or the absence of additional factors.

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Contribution of Syncytins and Other Endogenous Retroviral Envelopes to Human Placenta Pathologies

Bolze¹,

Mommert²,

Mallet

2017

Progress in Molecular Biology and Translational Science

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The immunosuppressive domain of the transmembrane envelope protein gp41 of HIV-1 binds to human monocytes and B cells

Cited by 5 publications

References 37 publications

Antigenic and immunosuppressive properties of a trimeric recombinant transmembrane envelope protein gp41 of HIV-1

Antigenic and immunosuppressive properties of a trimeric recombinant transmembrane envelope protein gp41 of HIV-1

Absence of IL-10 production by human PBMCs co-cultivated with human cells expressing or secreting retroviral immunosuppressive domains

Contribution of Syncytins and Other Endogenous Retroviral Envelopes to Human Placenta Pathologies

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