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)]-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.
Murakami
T
T
Department of Microbiology and Molecular Virology, Faculty of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
Zhang
T Y
TY
Koyanagi
Y
Y
Tanaka
Y
Y
Kim
J
J
Suzuki
Y
Y
Minoguchi
S
S
Tamamura
H
H
Waki
M
M
Matsumoto
A
A
Fujii
N
N
Shida
H
H
Hoxie
J A
JA
Peiper
S C
SC
Yamamoto
N
N
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D001665:Binding Sites; D002459:Cell Fusion; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D023181:Antimicrobial Cationic Peptides; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D010455:Peptides; D019718:Receptors, CXCR4; C076963:T22 protein, synthetic