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-1alpha-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.

• Authors: T Murakami, T Y Zhang, Y Koyanagi, Y Tanaka, J Kim, Y Suzuki, S Minoguchi, H Tamamura, M Waki, A Matsumoto, N Fujii, H Shida, J A Hoxie, S C Peiper, N Yamamoto
• Journal: Journal of virology (J Virol) Vol. 73 Issue 9 Pg. 7489-96 (Sep 1999) ISSN: 0022-538X [Print] United States
• PMID: 10438838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-HIV Agents
• Antimicrobial Cationic Peptides
• CXCL12 protein, human
• Chemokine CXCL12
• Chemokines, CXC
• HIV Envelope Protein gp120
• HIV envelope protein gp120 (305-321)
• Peptide Fragments
• Peptides
• Receptors, CXCR4
• T22 protein, synthetic

Topics

• Amino Acid Sequence
• Anti-HIV Agents (metabolism, pharmacology)
• Antimicrobial Cationic Peptides
• Binding Sites
• Cell Fusion
• Chemokine CXCL12
• Chemokines, CXC (metabolism)
• HIV Envelope Protein gp120 (metabolism)
• HIV-1 (drug effects, metabolism)
• HeLa Cells
• Humans
• Lipid Metabolism
• Molecular Sequence Data
• Peptide Fragments (metabolism)
• Peptides (metabolism, pharmacology)
• Receptors, CXCR4 (antagonists & inhibitors)
• Tumor Cells, Cultured