Due to the likely inability of currently approved drugs to attain sufficient concentrations in the central nervous system (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 HlV disease may suffer a persistent and disabling loss of cognitive and motor function referred to as AIDS dementia complex. HIV induced CNS dysfunction occurs with especially high frequency in HIV infected children, with 88% exhibiting CNS abnormalities. This proposal represents a collaborative effort between investigators at the University of Utah (PI) and University of Washington to improve CNS delivery of anti-HIV drugs used in combination therapy and to assess the value of such improvements in targeting the reservoirs of replicating HIV in the brain in an infant macaque model of neuro-AIDS. The problem is addressed along two broad fronts. First, the rational optimization of delivery of new anti-HIV drugs to the CNS will require a quantitative, mechanistic understanding of the substantial barriers to the brain uptake of these agents, particularly 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 will quantify the metabolic and transport processes in brain capillary endothelial cells which constitute the BBB for selected representatives of the dideoxynucleoside reverse-transcriptase (RT) inhibitor and protease inhibitor classes of anti-HIV agents. We are intrigued by preliminary data from the laboratories of the PI and elsewhere suggesting that both protease inhibitor and dideoxynucleoside RT inhibitor brain uptake may be restricted by members of the ATP binding cassette superfamily 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 hypothesis will be tested by performing in vivo pharmacokinetic and CNS uptake studies in both rodent and primate models. Finally, in aim 3 we will test the hypothesis in infant macaques infected with a neurovulent strain of HIV (HIV-2287 ) that improving the CNS delivery of didanosine and indinavir in combination therapy will in fact reduce HIV viral load in the CNS, reduce CNS damage, and diminish the role of the CNS as an HIV sanctuary. As observed in children, the infant macaques exhibit a higher incidence of neuro-AIDS than adults which can be characterized by delays in neurological development.
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