CNS DRUG DELIVERY STRATEGIES TARGETING THE HIV SANCTUARY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Due to the inability of currently approved drugs to attain sufficient concentrations in the CNS to completely suppress viral replication over a sustained period of time, concern is growing that the brain may serve as an HIV sanctuary. Adults with advanced HIV may suffer a loss of cognitive and motor function referred to as AIDS dementia complex. HIV induced CNS dysfunction occurs with high frequency in HIV infected children. The problem is addressed along two fronts. First, the rational optimization of delivery of new anti-HIV drugs to CNS will require a quantitative, mechanistic understanding of the role of the blood brain barrier (BBB). The BBB for these agents is not only a passive permeability barrier, but also consists of a host of metabolic-enzymes and efflux transporters localized within the brain capillaries. In aim 1, we quantify the metabolic and transport processes in brain capillary endothelial cells, which constitute the BBB for selected representatives of the dideoxynucleoside reverse-transcriptase inhibitor and protease inhibitor classes for anti-HIV agents. In our laboratories, preliminary data suggested that both protease inhibitor and RT inhibitor brain uptake may be restricted by members of the ATP binding cassette super-family of transporters within the BBB. Secondly, we wish to conduct in vivo studies aimed at improving therapy using existing drug combinations through enhanced CNS delivery. In aim 2, we will test the hypothesis that significantly higher CNS concentrations of anti-HIV agents (didanosine and indinavir) can be attained in combination therapy by modulation of the BBB to inhibit protease inhibitor efflux (with an inhibitor of p-glycoprotein) and by enhancing RT inhibitor uptake using an appropriate prodrug strategy (e.g., 6-Cl-ddp, a CNS-targeted prodrug of didanosine). This study will be done in vivo pharmacokinetic and CNS uptake studies in both rodent and primate models. In aim 3, we will test in infant macaques infected with a neurovirulent train of HIV-2 (HIV-2 287) whether improving the CNS delivery of didanosine and indinavir in combination therapy will reduce HIV viral load in the CNS, reduce CNS damage, and diminish the role of the CNS as an HIV sanctuary.