Maraviroc, the only CCR5 antagonist HIV inhibitor currently approved, has potent antiviral activity in treatment-experienced individuals infected with CCR5-using HIV-1 (R5 HIV-1). However, recent data from the MOTIVATE trials indicate that R5 HIV-1 can develop resistance to Maraviroc, underscoring the need for additional CCR5 antagonists. The CCR5 antagonist aplaviroc (APL) is active against Maraviroc-resistant viral strains but its clinical development has ended because of dose-related toxicity. Here we demonstrate that reduction of CCR5 density (receptors/cell) with the immunomodulatory drug rapamycin (RAPA) enhances the antiviral activity of APL, allowing lower, non-toxic effective doses. In the presence of RAPA, the concentration of APL required for 90% inhibition of R5 HIV-1 in primary CD4 lymphocytes was reduced by as much as 25-fold. We conclude that low doses of RAPA may reduce the anti-HIV effective dose of APL-derivatives currently in development and thus minimize their potential toxicity. Combinations of RAPA and CCR5 antagonists could provide an effective means to control drug-resistant R5 HIV in patients, most notably those infected with Maraviroc-resistant viruses.