An Immunomodulating Motif of the HIV-1 Fusion Protein Is Chirality-independent IMPLICATIONS FOR ITS MODE OF ACTION

作者：Faingold Omri; Ashkenazi Avraham; Kaushansky Nathali; Ben Nun Avraham; Shai Yechiel^*

来源：Journal of Biological Chemistry, 2013, 288(46): 32852-32860.

DOI：10.1074/jbc.M113.512038

• Autoimmune Diseases
• Immunosuppression
• Membrane Fusion
• Protein-Protein Interactions
• T-cell
• Viral Fusion Protein
• Membrane Recognition

Background: Recently, an immunosuppressive motif was identified in the HIV-1 envelope glycoprotein complex. Results: Both d- and l-stereoisomers of the motif inhibit T-cell receptor activation and preferentially bind T-cells over B-cells. Conclusion: The motif immunomodulates T-cells through interactions occurring within the membrane milieu. Significance: This study provides new insights into the immunosuppressive activity of the envelope glycoprotein complex and the molecular recognition within the membrane.
An immunosuppressive motif was recently found within the HIV-1 gp41 fusion protein (termed immunosuppressive loop-associated determinant core motif (ISLAD CM)). Peptides containing the motif interact with the T-cell receptor (TCR) complex; however, the mechanism by which the motif exerts its immunosuppressive activity is yet to be determined. Recent studies showed that interactions between protein domains in the membrane milieu are not always sterically controlled. Therefore, we utilized the unique membrane leniency toward association between d- and l-stereoisomers to investigate the detailed mechanism by which ISLAD CM inhibits T-cell activation. We show that a d-enantiomer of ISLAD CM (termed ISLAD d-CM) inhibited the proliferation of murine myelin oligodendrocyte glycoprotein (MOG)-(35-55)-specific line T-cells to the same extent as the l-motif form. Moreover, the d- and l-forms preferentially bound spleen-derived T-cells over B-cells by 13-fold. Furthermore, both forms of ISLAD CM co-localized with the TCR on activated T-cells and interacted with the transmembrane domain of the TCR. FRET experiments revealed the importance of basic residues for the interaction between ISLAD CM forms and the TCR transmembrane domain. Ex vivo studies demonstrated that ISLAD d-CM administration inhibited the proliferation (72%) and proinflammatory cytokine secretion of pathogenic MOG(35-55)-specific T-cells. This study provides insights into the immunosuppressive mechanism of gp41 and demonstrates that chirality-independent interactions in the membrane can take place in diverse biological systems. Apart from HIV pathogenesis, the d-peptide reported herein may serve as a potential tool for treating T-cell-mediated pathologies.

• 出版日期2013-11-15