Inhibitory Mechanism of the CXCR4 Antagonist T22 against Human Immunodeficiency Virus Type 1 Infection

Abstract

We recently reported that a cationic peptide, T22 ([Tyr 5,12 , Lys 7 ]-polyphemusin II), specifically inhibits human immunodeficiency virus type 1 (HIV-1) infection mediated by CXCR4 (T. Murakami et al., J. Exp. Med. 186:1389–1393, 1997). Here we demonstrate that T22 effectively inhibits replication of T-tropic HIV-1, including primary isolates, but not of non-T-tropic strains. By using a panel of chimeric viruses between T- and M-tropic HIV-1 strains, viral determinants for T22 susceptibility were mapped to the V3 loop region of gp120. T22 bound to CXCR4 and interfered with stromal-cell-derived factor-1α–CXCR4 interactions in a competitive manner. Blocking of anti-CXCR4 monoclonal antibodies by T22 suggested that the peptide interacts with the N terminus and two of the extracellular loops of CXCR4. Furthermore, the inhibition of cell-cell fusion in cells expressing CXCR4/CXCR2 chimeric receptors suggested that determinants for sensitivity of CXCR4 to T22 include the three extracellular loops of the coreceptor.