Potent Synergistic Anti-Human Immunodeficiency Virus (HIV) Effects Using Combinations of the CCR5 Inhibitor Aplaviroc with Other Anti-HIV Drugs

Abstract

Aplaviroc (AVC), an experimental CCR5 inhibitor, potently blocks in vitro the infection of R5-tropic human immunodeficiency virus type 1 (R5-HIV-1) at subnanomolar 50% inhibitory concentrations. Although maraviroc is presently clinically available, further studies are required to determine the role of CCR5 inhibitors in combinations with other drugs. Here we determined anti-HIV-1 activity using combinations of AVC with various anti-HIV-1 agents, including four U.S. Food and Drug Administration-approved drugs, two CCR5 inhibitors (TAK779 and SCH-C) and two CXCR4 inhibitors (AMD3100 and TE14011). Combination effects were defined as synergistic or antagonistic when the activity of drug A combined with B was statistically greater or less, respectively, than the additive effects of drugs A and A combined and drugs B and B combined by using the Combo method, described in this paper, which provides (i) a flexible choice of interaction models and (ii) the use of nonparametric statistical methods. Synergistic effects against R5-HIV-1(Ba-L) and a 50:50 mixture of R5-HIV-1(Ba-L) and X4-HIV-1(ERS104pre) (HIV-1(Ba-L/104pre)) were seen when AVC was combined with zidovudine, nevirapine, indinavir, or enfuvirtide. Mild synergism and additivity were observed when AVC was combined with TAK779 and SCH-C, respectively. We also observed more potent synergism against HIV-1(Ba-L/104pre) when AVC was combined with AMD3100 or TE14011. The data demonstrate a tendency toward greater synergism with AVC plus either of the two CXCR4 inhibitors compared to the synergism obtained with combinations of AVC and other drugs, suggesting that the development of effective CXCR4 inhibitors may be important for increasing the efficacies of CCR5 inhibitors.