Synergistic inhibition of R5 HIV-1 by maraviroc and CCR5 antibody HGS004 in primary cells: implications for treatment and prevention

Abstract

CCR5 blockers inhibit CCR5-tropic (R5) HIV-1, including strains resistant to other antiretrovirals. We demonstrate that the CCR5 antibody HGS004 and the CCR5 antagonist maraviroc have potent antiviral synergy against R5 HIV-1, translating into dose reductions of more than 10-fold for maraviroc and more than 150-fold for HGS004. These data, together with the high barrier of resistance to HGS004, suggest that combinations of maraviroc and HGS004 could provide effective preventive and therapeutic strategies against R5 HIV-1.

Figure 1. Antiviral interactions between HGS004 and MVC versus HGS004 and RAL against R5 HIV-1 in primary cells

PHA-activated PBMCs infected with HIV-1 BaL (a) or HIV-1 CC1/85 (b) using an MOI of 0.001 were cultured in the presence of the indicated drug concentrations. Virus production was measured on day 7 by p24 ELISA. Inhibition data from replicates were plotted using GraphPad Prism software and EC₅₀ values determined using variable slope non-linear regression analysis. MVC EC₅₀s for BaL and CC1/85 were 0.74 and 0.34 nM, respectively; whereas RAL EC₅₀s for BaL and CC1/85 were 4.3 and 1.1 nM, respectively (not shown). Upper panels: Dose response curves for HGS004, alone and in combination with MVC or RAL. At each MVC or RAL concentration, p24 inhibition by HGS004 was normalized to inhibition by MVC or RAL alone. Data points are means ± S.D. of duplicates. Lower panels: Three-dimensional analysis of viral inhibition by drug combinations. Percentage synergy obtained by each combination was plotted against HGS004 and MVC or RAL concentrations according to Prichard's synergy model. The 96% confidence interval synergy plots are shown. Percentage synergies at each 10% increment are shown in different color intensities. Note that the synergy plots included more drug concentrations than those shown in dose response curves. Data are representative of three independent experiments for BaL and two independent experiments for CC1/85, with PBMCs from different donors in each experiment.