Is there a future for antiviral fusion inhibitors?

Entry of human immunodeficiency virus type 1 (HIV-1) into cells is mediated by attachment of the envelope glycoproteins, gp120 and gp41, to the CD4 receptor and a chemokine receptor (CCR5 or CXCR4) and subsequent fusion of viral and cellular membranes. Several steps of the entry process can be targeted by drugs. Receptor antagonists prevent virus attachment and fusion inhibitors block conformational changes that are required for membrane fusion. The T20 peptide (Enfuvirtide, Fuzeon), which is homologous to part of the gp41-encoded fusion machinery, is the only clinically approved fusion inhibitor, but over the last decade new generations of T20-like peptides have been developed with improved potency and stability, as well as fusion inhibitors that target alternative gp41 domains. Here, we will review the field of HIV-1 fusion inhibitors.