A Similar Motif Shared by HIV-1 gp41 and TCRA Trans-Membrane Domains Exploited by the HIV Virus to Modulate T-Cell Proliferation

Abstract

The transmembrane domains (TMDs) of the T-cell receptor (TCR) play an important role in the assembly of the receptor complex. Previous studies have shown that the fusion peptide (FP) of HIV-1 inhibits T-cell activation and by that suppress the immune response against the virus. FP gains this activity by specifically binding to the TMD of TCRα and interfering with the assembly of the TCR complex We utilized in-silico testing of a TMD sequence library derived from virus protein sequences, and pin-pointed a nine amino-acid motif shared by a group of different viruses; this motif resembles the transmembrane domain of the α-subunit of the T-cell receptor (TCRα). The highest similarity was found within SIV and HIV glycoprotein 41 TMD (gp41 TMD). Previous studies have shown that stable interactions between TCRα and CD3 are localized to this nine amino acid motif within TCRα, and a peptide derived from it interfered and intervened in the TCR function when added exogenously. By combining biophysical and biochemical approaches we found that the gp41 TMD peptide co-localizes with CD3 within the TCR complex and inhibits T-cell proliferation in vitro. We also found that the inhibitory mechanism of gp41 TMD differs from that of FP. Disassociated from HIV, the gp41 TMD molecule provides a novel mechanism for down regulating undesirable responses and might be be used as an immunotherapeutic tool.