Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249

Abstract

We have assessed the potential of the fusion inhibitory peptide T-1249 for development as a vaginal microbicide to prevent HIV-1 sexual transmission. When formulated as a simple gel, T-1249 provided dose-dependent protection to macaques against high-dose challenge with three different SHIVs that used either CCR5 or CXCR4 for infection (the R5 virus SHIV-162P3, the X4 virus SHIV-KU1 and the R5X4 virus SHIV-89.6P), and it also protected against SIVmac251 (R5). Protection of half of the test animals was estimated by interpolation to occur at T-1249 concentrations of approximately 40-130 muM, whereas complete protection was observed at 0.1-2 mM. In vitro, T-1249 had substantial breadth of activity against HIV-1 strains from multiple genetic subtypes and in a coreceptor-independent manner. Thus, at 1 muM in a peripheral blood mononuclear cell-based replication assay, T-1249 inhibited all 29 R5 viruses, all 12 X4 viruses and all 7 R5X4 viruses in the test panel, irrespective of their genetic subtype. Combining lower concentrations of T-1249 with other entry inhibitors (CMPD-167, BMS-C, or AMD3465) increased the proportion of test viruses that could be blocked. In the PhenoSense assay, T-1249 was active against 636 different HIV-1 Env-pseudotyped viruses of varying tropism and derived from clinical samples, with IC(50) values typically clustered in a 10-fold range approximately 10 nM. Overall, these results support the concept of using T-1249 as a component of an entry inhibitor-based combination microbicide to prevent the sexual transmission of diverse HIV-1 variants.

Fig. 1.

Protection against SHIV vaginal challenge by vaginally applied T-1249. T-1249 was formulated in HMC gel and applied vaginally to macaques at the concentrations indicated on the x axis 30 min before challenge with SHIV-162P3 (A), SHIV-89.6P (B), or SHIV-KU1 (C). The proportion of the test animals that became infected at each T-1249 concentration is shown on the y axis. The figure in parentheses adjacent to each data point records the number of animals used to derive the recorded value.

Fig. 2.

Mean viral loads in control macaques and nonprotected T-1249 recipients. The plasma viral loads (VL) of all of the infected animals described in Fig. 1 are plotted on the y axis as mean log(VL) (RNA copies per milliliter) ± SEM over time (x axis) for control (open symbols) and test animals that were not protected by T-1249 at the various test doses (filled symbols). The challenge viruses were SHIV-162P3 (circles), SHIV-89.6P (squares), and SHIV-KU1 (triangles). The numbers of animals in the groups were: SHIV-162P3, 3 controls and 5 T-1249-treated; SHIV-89.6P, 2 controls and 7 T-1249-treated; SHIV-KU1, 4 controls and 4 T-1249-treated. The AUCs did not differ between the control and T-1249 groups for any of the challenge viruses.