The emerging role of fusion inhibitors in HIV infection.

Abstract

Fusion of HIV with its host cell requires the interaction of the viral envelope glycoprotein 120 (gp120) with the chemokine receptor CXCR4 [T cell-tropic (T-tropic) or X4 HIV strains] or CCR5 [macrophage-tropic (M-tropic) or R5 HIV strains] followed by a 'spring-loaded' action of the glycoprotein 41 (gp41) that ensures fusion of the viral and cellular lipid membranes and permits the viral nucleocapsid to enter the cell. The overall fusion process can be blocked by a number of compounds. These include siamycin analogues, SPC 3 (a synthetic peptide derived from the V3 domain of gp120), pentafuside (T 20, DP 178) [a synthetic peptide corresponding to amino acid residues 127 to 162 of gp41], the betulinic acid derivative RPR 103611, TAK 779 (a low molecular weight non-peptide CCR5 antagonist) and a number of compounds (T 22, T 134, ALX40-4C, CGP64222 and AMD 3100) that are targeted at the CXCR4 receptor. In particular, the bicyclam AMD 3100 has proved highly potent and selective as a CXCR4 antagonist that blocks the infectivity of X4 HIV strains in the nanomolar concentration range. The proof-of-concept that fusion inhibitors should be able to suppress viral replication in vivo has been demonstrated with pentafuside. Pentafuside and AMD 3100 have now proceeded to phase II clinical trials.