Neither ritonavir nor darunavir affect cell surface expression of tetherin or Vpu-mediated tetherin down-modulation

Protease inhibitors act late in the HIV-1 life cycle, following viral assembly at the cellular membrane, to inhibit protease-mediated viral maturation. Virological outcome associated with the use of protease inhibitors is correlated with levels of pharmacokinetic exposure, which can be affected by drug metabolism and active removal of drugs from target cells [1]. Protease inhibitors serve as a substrate for several membrane-spanning drug transporters and efflux pumps [2,3]. Ritonavir (RTV) is a protease inhibitor that can increase both intracellular and extracellular concentrations of other protease inhibitors, partly by direct inhibition of drug transporters or efflux pumps, and is used as a boosting agent for other drugs in antiretroviral therapy [4,5]. Controversy exists as to whether RTV also interferes with calpain-mediated proteasomal degradation of drug transporters and other cell-membrane proteins. Whereas calpain was shown to be inhibited by RTV in cell culture models [6], these results were not confirmed in biochemical studies [7].