ABSTRACT:
The purpose of this study was to determine whether any in vivo-generated T-20 resistance mutations affect sensitivity to T1249, a second generation fusion inhibitor. To this end, the sensitivity of patients isolates to T1249 was assessed. T 1249 is a hybrid synthetic peptide consisting of a 39 amino acid sequence derived from the highly conserved HR2 domains of HIV-1, HIV-2 and simian immunodeficiency virus (SIV) transmembrane (gp41) proteins. This peptide is a potent and selective inhibitor of HIV-1, HIV-2 and SIV fusion and infectivity. It is also effective against a variety of macrophage-tropic and drug-resistant isolates including T-20-resistant laboratory isolates. Clinical isolates were obtained from 74 antiretroviral-experienced patients treated with the fusion inhibitor T-20, in a recently concluded Phase II study (TRI-003). Isolates were cultured from PBMCs at day 0 and at day 28 of the study and evaluated for their sensitivity to T=20 and to T1249 in cMagi cell cultures. The emergence in vitro of T-20-resistant laboratory strains of HIV-1 containing specific genotypic changes in the HR1 domain of gp41 has been demonstrated. Similar mutations have been observed in isolates from some patients after T-20 monotherapy for up to 28 days. To date it has been very difficult to develop resistant isolates in vitro to T1249. In TRI-003 patients isolates culture prior to T-20 treatment, T1249 demonstrated an equal or more potent suppression of HIV-1 infection compared with T-20. The inhibitory capacity of T1249 against clinical isolates demonstrating T-20 phenotypic and genotypic resistance was similar to that seen with day 0 isolates. Thus, T1249 represents a new potent, selective, and specific fusion inhibitor which is equally potent against wild-type and T-20-resistant clinical isolates in vitro.
