It has been reported that the HIV-1 gp41 fusion peptide (FP) suppresses antigen-specific T-cell activation by targeting the T-cell receptor (TCR); VIR576,an optimized 20-mer peptide derived from the C-proximal subfragment of al-antitrypsin (al-AT) inhibits HIV-1 entry into the target cell by interacting with FP.First,we observed VIR576 inhibited antigen specific T cell activation but had no significant effect on non-antigen-specific T-cell activation,which bypasses the crosstalk between the CD3-signaling complex and TCR.Furthermore,using both CD4+T-cell line and primary isolating CD4+CD25T-cells,we found that VIR576 can also down-regulate antigen-specific CD4+T-cell activation.The immunosuppressive effect of VIR576,in addition to its HIV entry inhibitory activity,and given that HIV-1 infects CD4+T cells and the activated CD4+ T cells in mucosa are highly susceptible to HIV-1 infection,suggest that VIR576 is also a potential microbicide for prevention of sexual transmission of HIV.