Abstract
The transmembrane envelope protein gp41 of the human immunodeficiency virus HIV-1 plays an important role during infection allowing fusion of the viral and cellular membrane. In addition, there is increasing evidence that gp41 may contribute to the immunodeficiency induced by HIV-1. Recombinant gp41 and a synthetic peptide corresponding to a highly conserved domain in gp41, the immunosuppressive (isu) domain, have been shown to inhibit mitogen-induced activation of human peripheral blood mononuclear cells (PBMCs) and to increase release of IL-6 and IL-10 from these cells. We recently reported that a single mutation in the isu domain of gp41 abrogated the immunosuppressive properties and that HIV-1 sequences containing such abrogating mutations had never been isolated from infected individuals. Here, we studied the influence of the isu peptide on the release of 66 cytokines and the expression of 27,000 genes in PBMCs. Incubation of PBMCs with isu peptide homopolymers increased the expression of 16 cytokines among them IL-6 and IL-10, and decreased that of IL-2 and CXCL9. Interestingly, the extend of cytokine modulation was donor-dependent. Among the genes up-regulated were IL-6, IL-8, IL-10 but also MMP-1, TREM-1 and IL-1beta. Most importantly, genes involved in innate immunity such as FCN1 and SEPP1 were found down-regulated. Many changes in cytokine expression demonstrated in our experiments were also found in HIV-1 infected individuals. These data indicate that the isu domain of gp41 has a broad impact on gene expression and cytokine release and therefore may be involved in HIV-1 induced immunopathogenesis.
Highlights
The transmembrane envelope (TM) protein gp41 of the human immunodeficiency virus type 1 (HIV-1) facilitates - like the TM proteins of all retroviruses - the fusion of the viral and the cellular membranes during infection [1]
Synthetic Peptides Corresponding to the Isu Domain of gp41 of HIV-1 Inhibit Activation of peripheral blood mononuclear cells (PBMCs) and Modulate Expression of Cytokines
The difference in the IL-10 and IL-6 release by PBMCs treated with the isu peptide homopolymer and by untreated PBMCs was in all cases significant (Supplementary Figure S2a, b, c, d)
Summary
The transmembrane envelope (TM) protein gp of the human immunodeficiency virus type 1 (HIV-1) facilitates - like the TM proteins of all retroviruses - the fusion of the viral and the cellular membranes during infection [1] In addition to this function a contribution of TM proteins to the induction of the immunodeficiency was proposed on the basis of numerous findings: First, all retroviruses including HIV-1 and HIV-2 are immunosuppressive when present at a critical viral load in the infected host. This was studied in detail for gammaretroviruses such as the murine leukaemia virus (MuLV) and the feline leukaemia virus (FeLV). Since this gp was produced in E.coli, a contamination with endotoxin inducing IL-10 could not be excluded
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