Interaction between HIV gp41 fusion peptide and T cell receptor: putting the puzzle pieces back together

With regard to the paper by Bloch et al. (1), the authors address an interesting question concerning the molecular mechanisms of the interaction of the 33 amino acid HIV gp41 fusion peptide (FP1–33) and the T cell receptor (TCR). This peptide has been previously shown by Quintana et al. (2) to inhibit antigen specific T cell activation which makes its interaction with TCR both fundamentally and clinically important. To address this question, the authors used in their biophysical, cell and animal studies, several peptides including FP1–8 , FP5–13 , FP9–16 , FP1–33 , as well as the TCR core peptide (CP), a synthetic peptide corresponding to the transmembrane domain (TMD) of the TCR chain. Surprisingly, while the authors state that they identified the TCR/full-length FP (FP1-33) interactions at the molecular level, detailed experiments with N-terminal region peptides were performed but no experiments were done with any peptide(s) corresponding to the C-terminal half of the FP1–33. The interpretation of the obtained data and their discussion give the reader the impression that the FP1–33/TCR interaction is mostly driven by the interaction motif located in the 5–13 region of the FP1–33 and that the observed inhibitory activity of FP is provided only by this particular interaction. This impression can be misleading. In addition, several experimental results are not in agreement with this hypothesis, and these discrepancies are not addressed and discussed. Thus, following the author’s hypothesis that the 7 residue long 5–13 region is the only interaction motif that underlies binding of FP1–33 to the TCR and inhibiting T cell activation, it is difficult to explain why in T cell proliferation studies there is no inhibitory activity observed for FP1–16 at 1 and 5 g/ml whereas FP1–33 and FP5–13 are similarly active at these concentrations showing 50–60% of inhibition (ref 1:Figs. 1A, B, and 7). This discrepancy becomes more striking when one considers that at the same concentration expressed (in g/ml), there is 2and 4-fold difference in an amount of peptide molecules in FP1–16 and FP5–13 solutions, respectively, as compared with FP1–33. Thus, at this point, it is reasonable to suggest that FP1–33 has at least two interaction interfaces and that one of them is located in the C-terminal half of the peptide. However, this hypothesis was not considered, and using full-length FP1–33 in further experiments, the authors were stating that they are studying the potential interaction of the TCR TMD with FP1–16 (1). Thus, I feel it is important to point out for the reader that there is another possible molecular mechanism describing the action of HIV gp41 FP (throughout the text the term “FP” is used to designate a full-length FP, or FP1–33). It has been previously shown that FP inhibits antigenspecific T cell activation (2) in a manner surprisingly similar to that of TCR CP (3, 4). As mentioned above, TCR CP represents a sequence of the TCR TMD which has been shown to be critical for TCR assembly and function (5) and to interact with the TMDs of the signaling CD3 ε and subunits (6), thus maintaining the integrity of the TCR in resting T cells. TCR TM peptides capable of inhibiting antigen-stimulated TCRmediated T cell activation were first reported in 1997 (3). Since that time, despite extensive basic and clinical studies of these peptides, the molecular mechanisms of action of these clinically relevant peptides have not been elucidated until 2004 when a newly developed model of immune signaling, the signaling chain homooligomerization (SCHOOL) model, was first introduced (7). Considering the close similarity in patterns of inhibition of T cell activation and immunosuppressive activity observed for FP (2) and CP (4), the SCHOOL model reasonably suggests a similar molecular mechanism of action for TCR TM peptides and HIV gp41 FP (7, 8). Primary sequence analysis of these two peptides shows different primary sequences but a similarity in charged or polar residue distribution patterns with two positively charged residues spaced apart by 4 (CP) or 8 (FP) amino acids. For CP, Arg and Lys residues are well-known to mediate the interaction between recognition TCR subunit and signaling CD3 ε and subunits (6). Importantly, for FP, both arginines are located in the C-terminal half, suggesting that this sequence could be important for the interaction with the TCR. Figure 1 shows a potential mode of action of CP and FP as proposed by the SCHOOL model. Briefly, the CP and FP compete with the TCR chain for binding to CD3 ε and heteroand homodimers, respectively, thus resulting in transmembrane “disconnection” of the signaling subunits from the remaining receptor complex (Fig. 1). This mechanism of FP action suggests the existence of an interaction interface in the C-terminal half of the peptide. It