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Antimicrobial Agents and Chemotherapy, June 2008, p. 2111-2119, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01299-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,¹ Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Departments of Infectious Diseases and Hematology, Kumamoto 860-8556, Japan,² Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,³ Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan,⁴ Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan⁵

Received 8 October 2007/ Returned for modification 19 November 2007/ Accepted 21 March 2008

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.

Published ahead of print on 31 March 2008.

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