Modulation of Cytokine Release and Gene Expression by the Immunosuppressive Domain of gp41 of HIV-1

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.

HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes

“…Furthermore, HERV-K Env on the virion surface could provide the ability to influence cytokine production and induce immunosuppression, as recently described (58); this characteristic also has been reported for other retroviruses, including HIV-1 gp41 (59,60).…”

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

“…The advantage of the gp41 produced here in human 293 cells in contrast to many other gp41 produced in bacteria is that it is free of endotoxin. Some of the up-regulated cytokines and genes had been reported previously after incubation of homopolymers of peptides corresponding to the Isu domain with human PBMCs, but this study is a significant extension of the previous study [17]. Among the proteins reported for the first time, IL-1Ra represents a well-known immunosuppressive cytokine able to inhibit the pro-inflammatory responses stimulated by binding of IL-1β to the IL-1 receptor [38, 39].…”

Treatment of Ebola virus infections with inhibitors of TLR4

“…In contrast, the corresponding peptide of the Reston EBOV, which is pathogenic in monkeys but not in humans, has a single mutation and did not show these effects with human cells [49]. Similarly, single mutations in the immunosuppressive domain of different retroviruses including HIV-1 also abrogated their modulating properties [47,48,50]. Furthermore, the glycoprotein of the EBOV inhibits T cell proliferation [51] as was previously demonstrated for retroviruses, their transmembrane envelope proteins and the synthetic peptide corresponding to the immunosuppressive domain (for review see [47]).…”

“…2) [44][45][46]. Synthetic peptides corresponding to the immunosuppressive domain of various retroviruses including HIV-1, their purified transmembrane envelope protein and non-infectious retroviruses inactivated by different methods, all induced similar changes in cytokine expression (Table 1) (for review see [47,48]. In agreement with this, synthetic peptides corresponding to the immunosuppressive domains of ZEBOV, the Sudan EBOV and the Marburg virus, all of which are pathogenic in humans and monkeys, inhibited CD4 and CD8 cell cycle progression, decreased IL-2 expression and increased IL-10 expression [49].…”