Specific Aims Neurological complications of HIV-1/AIDS persist despite HAART therapies. Current knowledge identifies several sources of neuronal aggravation: (1) direct virus infection of astrocytes and microglial cells;(2) infiltratin of virus-infected monocyte/macrophages;(3) cytokine dysregulation indirectly affecting nerve cells;(4) breakdown of the blood-brain-barrier;(5) abnormal antigen-presentation leading to autoimmunity;(6) apoptotic suicide of neuronal cells and (7) toxins associated with HAART therapies. Novel antiretroviral therapeutic approaches are urgently needed for individuals suffering from NeuroAIDS. This goal is to investigate and develop a novel therapeutic for the treatment of NeuroAIDS. Based upon preliminary studies, this small molecule exhibits a unique molecular action resulting in reductions to the proviral reservoir together with direct inhibition f virus productions. Since the compound is blood-brain barrier penetrable, it potentially affords adjunctive therapeutic value specifically appropriate for central nervous system (CNS) lentivirus burdens. The working hypothesis is that FX101 is a novel antiretroviral compound especially suited for NeuroAIDS, uniquely targeting lentiviral nucleocapsid proteins. Using the FIV model, we seek to investigate antiviral efficacies with emphasis to the CNS compartment and to relate these findings to the proposed mechanism of action. The proposed studies are designed to accomplish four goals: 1) Establish safety and pharmacokinetics of FX101 in cats, including penetration into the CNS. 2) Measure effects of FX101 on FIV burden in plasma, CSF, T-cell subsets and brain tissue. 3) Evaluate the uptake and distribution of FX101 in macrophages and its ability to suppress virus production. 4) Examine and compare virion progeny and nucleocapsid proteins produced during exposure to FX101. We propose to examine pharmacokinetic, safety and antiretroviral efficacy of this novel compound towards application of a CNS-relevant antiretroviral compound for HIV.
This research proposal examines both efficacy and a novel mechanism of action of a blood-brain- barrier penetrable therapeutic useful in the treatment of HIV/AIDS, reducing proviral reservoirs in peripheral blood mononuclear cells and cerebrospinal measures of viremia. It is expected that this work will reduce the burden of neurological diseases impacting the central nervous system as a consequence of lentiviral infections and associated pathologies, leading to better treatments for HIV/AIDS-Associated Neuropsychological Disorders.
