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. 2006 Oct;50(10):3289-96.
doi: 10.1128/AAC.00699-06.

Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1

Jose D Murga  1 , Michael Franti, Daniel C Pevear, Paul J Maddon, William C Olson
Affiliations

Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1

Jose D Murga et al. Antimicrob Agents Chemother. 2006 Oct.

Abstract

The chemokine receptor CCR5 provides a portal of entry for human immunodeficiency virus type 1 (HIV-1) into susceptible CD4(+) cells. Both monoclonal antibody (MAb) and small-molecule CCR5 inhibitors have entered human clinical testing, but little is known regarding their potential interactions. We evaluated the interactions between CCR5 MAbs, small-molecule CCR5 antagonists, and inhibitors of HIV-1 gp120, gp41, and reverse transcriptase in vitro. Inhibition data were analyzed for cooperative effects using the combination index (CI) method and stringent statistical criteria. Potent, statistically significant antiviral synergy was observed between the CCR5 MAb PRO 140 and the small-molecule CCR5 antagonists maraviroc (UK-427,857), vicriviroc (SCH-D), and TAK-779. High-level synergy was observed consistently across various assay systems, HIV-1 envelopes, CCR5 target cells, and inhibition levels. CI values ranged from 0.18 to 0.64 and translated into in vitro dose reductions of up to 14-fold. Competition binding studies revealed nonreciprocal patterns of CCR5 binding by MAb and small-molecule CCR5 inhibitors, suggesting that synergy occurs at the level of receptor binding. In addition, both PRO 140 and maraviroc synergized with the chemokine RANTES, a natural ligand for CCR5; however, additive effects were observed for both small-molecule CCR5 antagonists and PRO 140 in combination with other classes of HIV-1 inhibitors. The findings provide a rationale for clinical exploration of MAb and small-molecule CCR5 inhibitors in novel dual-CCR5 regimens for HIV-1 therapy.

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Figures

FIG. 1.
FIG. 1.
Dose-response curves for inhibition of HIV-1JR-FL envelope-mediated membrane fusion by combinations of CCR5 inhibitors. Dilutions were analyzed in triplicate wells, and the data points depict the means and standard deviations of replicates. (A) PRO 140 and maraviroc (UK-427,857) were tested individually and in a 1:1 fixed molar ratio over the indicated range of concentrations. In the experiment whose results are depicted, IC50 and IC90 values were 2.9 nM and 11 nM for PRO 140, 5.0 nM and 21 nM for maraviroc, and 2.1 nM and 4.6 nM for the combination, respectively. CI50 and CI90 values were 0.58 and 0.32, respectively. (B) Vicriviroc (SCH-D) and maraviroc were tested individually and in a 1:1 fixed molar ratio over the indicated range of concentrations. In the experiment whose results are depicted, IC50 and IC90 values were 5.5 nM and 34 nM for vicriviroc, 9.7 nM and 59 nM for maraviroc, and 6.1 nM and 31 nM for the combination, respectively. CI50 and CI90 values were 0.87 and 0.73, respectively.
FIG. 2.
FIG. 2.
Inhibition of PRO 140-PE binding to CEM.NKR-CCR5 cells by unlabeled PRO 140, maraviroc, and vicriviroc. CEM.NKR-CCR5 cells were incubated with various concentrations of unlabeled PRO 140, maraviroc, or vicriviroc for 30 min at room temperature in PBSA buffer prior to the addition of 5 nM PRO 140-PE for an additional 30 min. Cells were washed and then analyzed by flow cytometry for both the MFI of binding and the percentage of cells gated for positive binding of PRO 140-PE. Inhibition was assessed on the basis of both MFI (A) and the percentage of cells gated (B).
FIG. 3.
FIG. 3.
Inhibition of 3H-maraviroc binding by unlabeled maraviroc, vicriviroc, and PRO 140. (A) CEM.NKR-CCR5 cells were preincubated with various concentrations of unlabeled maraviroc, vicriviroc, or PRO 140 for 30 min in PBSA buffer at ambient temperature prior to the addition of 2 nM 3H-maraviroc for an additional 30 min. Cells were washed and then analyzed for radioactivity by scintillation counting. (B) The stability of maraviroc binding under the assay conditions was examined by preincubating CEM.NKR-CCR5 cells with 2 nM 3H-maraviroc prior to washing, the addition of unlabeled compounds for 30 min, and processing as described above.
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References

    1. Alkhatib, G., C. Combadiere, C. C. Broder, Y. Feng, P. E. Kennedy, P. M. Murphy, and E. A. Berger. 1996. CC CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272:1955. - PubMed
    1. Allaway, G. P., K. L. Davis-Bruno, G. A. Beaudry, E. B. Garcia, E. L. Wong, A. M. Ryder, K. W. Hasel, M.-C. Gauduin, R. A. Koup, J. S. McDougal, and P. J. Maddon. 1995. Expression and characterization of CD4-IgG2, a novel heterotetramer which neutralizes primary HIV-1 isolates. AIDS Res. Hum. Retrovir. 11:533-539. - PubMed
    1. Baba, M., O. Nishimura, N. Kanzaki, M. Okamoto, H. Sawada, Y. Iizawa, M. Shiraishi, Y. Aramaki, K. Okonogi, Y. Ogawa, K. Meguro, and M. Fujino. 1999. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA 96:5698-5703. - PMC - PubMed
    1. Basavapathruni, A., C. M. Bailey, and K. S. Anderson. 2004. Defining a molecular mechanism of synergy between nucleoside and nonnucleoside AIDS drugs. J. Biol. Chem. 279:6221-6224. - PubMed
    1. Borkow, G., D. Arion, M. A. Wainberg, and M. A. Parniak. 1999. The thiocarboxanilide nonnucleoside inhibitor UC781 restores antiviral activity of 3′-azido-3′-deoxythymidine (AZT) against AZT-resistant human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 43:259-263. - PMC - PubMed

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