Characterization of the interacting domain of the HIV-1 fusion peptide with the transmembrane domain of the T-cell receptor.

HIV infection is initiated by the fusion of the viral membrane with the target T-cell membrane. The HIV envelope glycoprotein, gp41, contains a fusion peptide (FP) in the N terminus that functions together with other gp41 domains to fuse the virion with the host cell membrane. We recently reported that FP co-localizes with CD4 and T-cell receptor (TCR) molecules, co-precipitates with TCR, and inhibits antigen-specific T-cell proliferation and pro-inflammatory cytokine secretion. Molecular dynamic simulation implicated an interaction between an alpha-helical transmembrane domain (TM) of the TCRalpha chain (designated CP) and the beta-sheet 5-13 region of the 16 N-terminal amino acids of FP (FP(1-16)). To correlate between the theoretical prediction and experimental data, we synthesized a series of mutants derived from the interacting motif GALFLGFLG stretch (FP(5-13)) and investigated them structurally and functionally. The data reveal a direct correlation between the beta-sheet structure of FP(5-13) and its mutants and their ability to interact with CP and induce immunosuppressive activity; the phenylalanines play an important role. Furthermore, studies with fluorescently labeled peptides revealed that this interaction leads to penetration of the N terminus of FP and its active analogues into the hydrophobic core of the membrane. A detailed understanding of the molecular interactions mediating the immunosuppressive activity of the FP(5-13) motif should facilitate evaluating its contribution to HIV pathology and its exploitation as an immunotherapeutic tool.