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Reduction of CCR5 with Low-Dose Rapamycin Enhances the Antiviral Activity of Vicriviroc Against Both Sensitive and Drug-Resistant HIV-1

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Reduction of CCR5 with Low-Dose Rapamycin Enhances the Antiviral Activity of Vicriviroc Against Both Sensitive and Drug-Resistant HIV-1 Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1 Alonso Heredia1,2, Olga Latinovic1, Robert C. Gallo2, Gregory Melikyan, Marv Reitz, Nhut Le, and Robert R. Redfield2 Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201 Contributed by Robert C. Gallo, October 27, 2008 (sent for review August 25, 2008) Vicriviroc (VCV) is a chemokine (C-C motif) receptor 5 (CCR5) We previously have demonstrated that low doses of the antagonist with potent anti-HIV activity that currently is being transplant drug rapamycin (RAPA) reduce CCR5 density, in- evaluated in phase III clinical trials. In the present study, donor hibit R5 HIV-1, and enhance T-20 antiviral activity (14, 15). In CCR5 density (CCR5 receptors/CD4 lymphocytes) inversely corre- the present study we show that the combination of RAPA and /VCV has considerable antiviral synergy. Moreover, the RAPA ؍ lated with VCV antiviral activity (Spearman’s correlation test; r Low doses of the transplant drug rapamycin VCV combination is active against VCV-resistant HIV-1. These .(0.0034 ؍ P ,0.746 (RAPA) reduced CCR5 density and enhanced VCV antiviral activity. findings suggest the use of RAPA in patients as a strategy for In drug interaction studies, the RAPA/VCV combination had con- enhancing the antiviral activity of VCV and perhaps of other siderable antiviral synergy (combination indexes of 0.1–0.04) in CCR5 antagonists as well. both multicycle and single-cycle infection of lymphocytes. The synergy between RAPA and VCV translated into dose reduction Results indexes of 8- to 41-fold reductions for RAPA and 19- to 658-fold Impact of CCR5 Density on the Antiviral Activity of VCV. We first reductions for VCV. RAPA enhanced VCV antiviral activity against evaluated the effect of CCR5 levels on the antiviral activity of both B and non-B clade isolates, potently suppressing clade G VCV using cell lines JC10 (ϳ 2 ϫ 103 CCR5/cell) and JC57 (ϳ viruses with reported reduced sensitivities to VCV and to the 9 ϫ 103 CCR5/cell), which express CD4 levels similar to those in licensed CCR5 antagonist maraviroc. Importantly, RAPA reduction normal CD4 T cells and whose CCR5 densities correspond to the of CCR5 density in lymphocytes sensitized VCV-resistant strains to approximate lower and upper levels of CCR5 expression in ϳ VCV, inhibiting virus production by 90%. We further demon- donors (9–12). We infected each clone with the R5 HIV-1 strains strated the role of CCR5 density on VCV activity against resistant JRFL and CC1/85 (multiplicity of infection, MOI ϭ 0.01) in the virus in donor lymphocytes and in cell lines expressing varying presence of varying concentrations of VCV (0.03–30 nM) for 3 h. CCR5 densities. Together, these results suggest that low doses of For comparison, cells also were infected in the presence of the RAPA may increase the durability of VCV-containing regimens in reverse transcriptase inhibitor efavirenz (0.003–3 nM). On day 4 patients by enhancing VCV viral suppression, by allowing the use after infection, HIV-1 p24 levels in the culture supernatants of lower doses of VCV with reduced potential for toxicity, and by were determined by ELISA (National Cancer Institute). VCV controlling emerging VCV-resistant variants. inhibited HIV-1 JRFL replication in the JC-10 and JC-57 clones with EC values of 0.02 and 0.25 nM, respectively (Fig. 1A). In chemokine receptor 5 antagonists ͉ coreceptor density ͉ HIV resistance ͉ 50 contrast, EC values for efavirenz were similar (less than vicriviroc resistance ͉ maraviroc 50 twofold change) in both cell lines (data not shown). Similar results were obtained with HIV-1 CC1/85 (data not shown). ighly active antiretroviral therapy (HAART) has improved These data suggest that variations in CCR5 density within the Htreatment of HIV-1 infected individuals considerably (1). range observed in most individuals (ϳ 2 ϫ 103-1 ϫ 104 receptors/ However, the success of current therapies is limited by the CD4 T cell) greatly affect the antiviral activity of VCV. emergence of drug-resistant strains, the need for sustained We next evaluated the effect of CCR5 density on VCV activity adherence to complex regimens, and the potential for drug in infectivity assays using lymphocytes from different donors as toxicity (2, 3). The two new antiretroviral classes of integrase and target cells. Coreceptor CCR5 density was quantified for each entry inhibitors may help overcome some of the current limita- donor cell by quantitative flow cytometry analysis. Cells were tions of HAART (4, 5). Entry inhibitors are especially attractive infected with the R5 strain HIV-1 JRFL (MOI ϭ 0.001) for 3 h because they target HIV at the earliest step of the viral cycle and in the presence of varying concentrations of VCV. Virus pro- are effective against strains resistant to inhibitors of protease and duction was measured on day 5 after infection by p24 levels in reverse transcriptase. Entry inhibitors interfere with HIV bind- the supernatants. Results are summarized in Fig. 1B. Among ing to CD4 receptor (attachment inhibitors) or chemokine (C-C different donors, CCR5 density on CD4 T cells varied between 1.9 motif) receptor 5 (CCR5)/chemokine (C-X-C- motif) receptor 4 and 7 ϫ 103 CCR5 receptors/cell. In contrast, measured CD4 (CXCR4) coreceptors (coreceptor antagonists) or by preventing density values were similar among the donors (range of 22.4–27.0 ϫ fusion between cellular and viral membranes (fusion inhibitors) (5). Currently, the fusion inhibitor T-20 (enfuvirtide) and the CCR5 antagonist maraviroc (Selzentry) are the only licensed Author contributions: A.H., O.L., R.C.G., G.M., and R.R.R. designed research; A.H., O.L., and entry inhibitors (6, 7). The CCR5 antagonist vicriviroc (VCV) N.L. performed research; A.H., O.L., G.M., M.R., and R.R.R. analyzed data; and A.H. and presently is in phase III clinical trials (8). Coreceptor CCR5 R.R.R. wrote the paper. antagonists inhibit CCR5-tropic HIV-1 (referred to as ‘‘R5 The authors declare no conflict of interest. HIV-1’’) strains, which are responsible for most transmissions 1These authors contributed equally to this work. and generally are present throughout the course of infection. In 2To whom correspondence may be addressed. E-mail: [email protected], normal individuals, CCR5 density (receptors/cell) on CD4 lym- [email protected], or rredfi[email protected]. 3 3 phocytes ranges between ϳ 2 ϫ 10 and ϳ 10 ϫ 10 (9–12), and This article contains supporting information online at www.pnas.org/cgi/content/full/ this variation influences disease progression and response to 0810843106/DCSupplemental. therapy in HIV-1 infection (11, 13). © 2008 by The National Academy of Sciences of the USA 20476–20481 ͉ PNAS ͉ December 23, 2008 ͉ vol. 105 ͉ no. 51 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0810843106 Downloaded by guest on September 28, 2021 Fig. 1. CCR5 density impacts the antiviral activity of VCV. (A) Effect of CCR5 density on VCV antiviral activity in cell lines. The HeLa clones HI-JC10 and HI-JC57 were infected with the R5 strain HIV-1 JRFL in the presence of the indicated concentrations of VCV. Virus production was measured by p24 ELISA on day 4 after infection, and data were used to determine EC50 values. Data are means Ϯ SD of two experiments. (B) CCR5 density on primary CD4ϩ cells correlates with antiviral activity of VCV. Activated PBMCs from different donors were subjected to flow cytometry analysis and infection with the R5 strain HIV-1 JRFL in the presence of varying concentrations of VCV. On day 5 Fig. 2. Effect of RAPA on the antiviral activities of VCV and efavirenz in a after infection, virus production was determined by measuring p24 levels. VCV multicycle replication assay. RAPA-pretreated PBMCs were infected with EC50 values were plotted against CCR5 density values on the day of infection. HIV-1 JRFL in the presence of the indicated concentrations of VCV and efa- Line fit was done by linear regression. r, Spearman correlation coefficient. virenz. (A) Virus production was determined by measuring p24 levels on day 5 after infection. (B) Cell viability was determined by the MTT assay on day 5 after infection. Data (means Ϯ SD) are from one representative experiment of 3 10 CD4 receptors/cell) (data not shown). These density values for three independent experiments. CCR5 and CD4 are within the ranges reported by others (9–12). Interestingly, VCV EC50 values varied ϳ 20-fold among the dif- ferent donors and correlated positively with CCR5 densities (Spear- indexes (CI) at RAPA/VCV ratios of 3/10 and 3/100. We chose man’s correlation test; r ϭ 0.746, P ϭ 0.0034). A similar correlation these drug ratios based on previous determinations of EC50 between CCR5 density and VCV EC50 was obtained using HIV-1 values for each drug. Data were analyzed using the CalcuSyn CC1/85 (data not shown). In a control experiment assessing the software, and results are summarized in Table S1. When used donor cells’ ability to support virus replication, we infected cells alone, RAPA and VCV inhibited virus replication with dose at with the X4 strain HIV-1 IIIb and found p24 values varying by less 50% inhibition (Dm, equivalent to EC50) values of 0.25 and 2.78 than threefold among the different donors (data not shown). nM, respectively. However, when combined at a RAPA/VCV Together, these results using donor cells (Fig. 1B) suggest that ratio of 3/10, the Dm value for RAPA was reduced to 0.03 nM, variations of CCR5 density among individuals considerably affect and the Dm value for VCV was reduced to 0.10 nM.
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