Rapamycin enhances aplaviroc anti-HIV activity: implications for the clinical development of novel CCR5 antagonists.
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.
Latinovic
Olga
O
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Heredia
Alonso
A
Gallo
Robert C
RC
Reitz
Marv
M
Le
Nhut
N
Redfield
Robert R
RR
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D054659:Diketopiperazines; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000494:pharmacology* / Q000633:toxicity; D020123:Sirolimus / Q000494:pharmacology* / Q000633:toxicity; D013141:Spiro Compounds / Q000494:pharmacology* / Q000633:toxicity
D019380:Anti-HIV Agents; D001565:Benzoates; D054659:Diketopiperazines; D010879:Piperazines; D013141:Spiro Compounds; C499671:aplaviroc; D020123:Sirolimus