Inhibitory mechanism of the CXCR4 antagonist t22 against human immunodeficiency virus type 1 infection

We recently reported that a cationic peptide, T22 ([Tyr(5,12), Lys(7)]-poly phemusin II), specifically inhibits human immunodeficiency virus type 1 (HI V-1) infection mediated by CXCR4 (T. Murakami ct 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 str ains. By using a panel of chimeric viruses between T- and M-tropic HIV-1 st rains, viral determinants for T22 susceptibility were mapped to the V3 loop region of gp120. T22 bound to CXCR4 and interfered with stromal-cell-deriv ed factor-1 alpha-CXCR4 interactions in a competitive manner. Blocking of a nti-CXCR4 monoclonal antibodies by T22 suggested that the peptide interacts with the N terminus and two of the extracellular loops of CXCR4. Furthermo re, the inhibition of cell-cell fusion in cells expressing CXCR4/CXCR2 chim eric receptors suggested that determinants for sensitivity of CXCR4 to T22 include the three extracellular loops of the coreceptor.