Since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990's for treatment of human immunodeficiency virus type 1 (HIV-1) infection, overall incidence rates of associated neurological maladies have declined. Unfortunately, the HIV-associated prevalence of both central nervous system (CNS) and peripheral nervous system (PNS) disorders is on the rise, suggesting a failure of antiretroviral therapies to protect neurological tissues despite reducing viral replication. Novel antiretroviral therapeutic approaches are urgently needed for individuals suffering from NeuroAIDS. Most antiretrovirals cannot penetrate into the CNS where both direct and indirect viral burden lead to neuronal damage. Although neurons do not directly support HIV infection, soluble factors and neurotoxins produced by CNS-resident infected cells - such as microglia and astrocytes - are known to lead to neuronal death. Additionally, viral and bacterial proteins can lead to neuronal death through inflammatory responses of CNS- resident cells, even in the absence of direct viral infection. This proposal aims to develop a novel therapeutic suitable for such CNS complications of HIV infection. FX101 is a novel potential antiretroviral therapeutic especially suited for NeuroAIDS, as evidenced by evaluation of virological, immunological and soluble factors in vitro and in vivo, together with its capacity to penetrate the CNS compartment.
Specific aims of this project are: 1) demonstrate preclinical safety outcomes and central nervous system uptake of FX101 in vivo; 2) examine in vitro responses of microglial and macrophage cells to FX101 both directly and in concert with viral protein or lipopolysaccharide activation;and 3) evaluate translational therapeutic efficacy of FX101 using human HIV-infected ex vivo whole blood cultures The proposed work will develop along two years and will be continuously evaluated toward the goal of filing an IND application and commercialization of the therapeutic.
This research proposal examines preclinical toxicological studies and human translational efficacy of a novel blood-brain-barrier penetrable therapeutic for the treatment of HIV/AIDS, with or without drug abuse. 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.
