Enhancing the efficacy of HIV-1 protease inhibitors: In vitro and in vivo studies

The objective of this study was to determine the factors influencing the central nervous system (CNS) distribution of HIV-1 Protease Inhibitors. The present study suggests that HIV-1 PIs are substrates of p-glycoprotein (P-gp) and to a limited extent MRP1 although other organic anion transport proteins, including the various isoforms of the MRP family may also be responsible for the efflux of PIs in the brain.; Initially, a P-gp ATPase assay was utilized to screen various HIV-1 protease inhibitors ATPase activity to increase our understanding into the possible advantages or disadvantages of co-administration of P-gp inhibitors or other substrates of P-gp. Furthermore, using inhibitors of P-gp, accumulation of PIs was shown to increase in cell monolayers (Figs. 3-1 and 3-3). The brain distribution of the HIV-1 Protease Inhibitor nelfinavir was also shown to increase when co-administered with valspodar an inhibitor of P-gp (Figs. 3-5 and 3-6).; In other in vitro and in vivo studies a novel copolymer, PluronicRTM P85, was chosen as the P-gp inhibitor based upon previous studies demonstrating that P85 treatment increased the permeability of P-gp substrates across primary cultures of bovine brain microvessel endothelial cells. The HIV-1 protease inhibitor nelfinavir was chosen due its use in current HAART regimens and poor CNS permeability. Our in vitro study demonstrated that nelfinavir alone and with P85 significantly lowered HIV-1 replication in human MDM (measured by RT activity) when compared to control untreated cells (Fig. 5-1). Additionally, our in vivo efficacy studies exhibited unexpected results that showed the previously unknown antiviral effect of P85 when administered independently of nelfinavir.; The studies presented in this dissertation characterizes the processes that influence HIV-1 PI transport in the central nervous system. The information provided will aid in increasing HIV-1 PIs distribution in the CNS a known HIV-1 sanctuary site. Moreover, these studies demonstrate that novel compounds may be another way to combat HIV-1 infection.