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Antimicrobial Agents and Chemotherapy, July 2007, p. 2489-2496, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01602-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Rapamycin Reduces CCR5 Density Levels on CD4 T Cells, and This Effect Results in Potentiation of Enfuvirtide (T-20) against R5 Strains of Human Immunodeficiency Virus Type 1 In Vitro{triangledown}

Alonso Heredia, Bruce Gilliam, Olga Latinovic, Nhut Le, Douty Bamba, Anthony DeVico, Gregory B. Melikyan, Robert C. Gallo, and Robert R. Redfield*

Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201

Received 22 December 2006/ Returned for modification 30 January 2007/ Accepted 27 April 2007

The CCR5 chemokine receptor plays a pivotal role in human immunodeficiency virus type 1 (HIV-1) infection. Several studies have suggested that CCR5 density levels in individuals are rate limiting for infection. In addition, CCR5 density levels influence the antiviral activity of the HIV-1 fusion inhibitor enfuvirtide (T-20) against R5 strains. In the present study we demonstrate that rapamycin (RAPA), a drug approved for the treatment of renal transplantation rejection, reduces CCR5 density levels on CD4 T cells and inhibits R5 HIV-1 replication. In addition, RAPA increased the antiviral activity of T-20 against R5 strains of the virus in a cell-cell fusion assay and as shown by quantification of early products of viral reverse transcription. Median-effect analysis of drug interaction between RAPA and T-20 in infectivity assays using donor peripheral blood mononuclear cells demonstrated that the RAPA-T-20 combination is synergistic against R5 strains of HIV-1 and this synergy translates into T-20 dose reductions of up to ~33-fold. Importantly, RAPA effects on replication levels and T-20 susceptibility of R5 strains of HIV-1 were observed at drug concentrations that did not inhibit cell proliferation. These results suggest that low concentrations of RAPA may potentiate the antiviral activity of T-20 against R5 strains of HIV-1, which are generally present throughout the course of infection and are less sensitive to T-20 inhibition than are X4 strains.

* Corresponding author. Mailing address: Institute of Human Virology, 725 W. Lombard St., Baltimore, MD 21201. Phone: (410) 706-4613. Fax: (410) 706-4619. E-mail: redfield{at}umbi.umd.edu

{triangledown} Published ahead of print on 7 May 2007.

Antimicrobial Agents and Chemotherapy, July 2007, p. 2489-2496, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01602-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Heredia, A., Latinovic, O., Gallo, R. C., Melikyan, G., Reitz, M., Le, N., Redfield, R. R. (2008). Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1. Proc. Natl. Acad. Sci. USA 105: 20476-20481 [Abstract] [Full Text]  


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