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. , ,
Public Health Relevance: 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.
Thesaurus Terms: Aids Virus;Aids Neuropathy;Aids/Hiv;Aids/Hiv Problem;Acquired Immune Deficiency Syndrome Virus;Acquired Immunodeficiency Syndrome Virus;Affect;Anti-Retroviral Agents;Antigen Presentation;Antiretroviral Agents;Antiretroviral Therapy, Highly Active;Antiviral Agents;Antiviral Drugs;Antivirals;Apoptotic;Astrocytes;Astrocytus;Astroglia;Autoimmune;Autoimmune Process;Autoimmune Status;Autoimmunity;Bacterial Gene Proteins;Bacterial Proteins;Blood - Brain Barrier Anatomy;Blood Monocyte;Blood-Brain Barrier;Body Tissues;Cells;Central Nervous System;Cessation Of Life;Clinical Trials;Clinical Trials, Unspecified;Death;Disease;Disorder;Dose;Drug Abuse;Drugs, Investigational;Evaluation;Exhibits;Fda;Fiv;Flr;Ftlv;Failure (Biologic Function);Feline Immunodeficiency Virus;Feline T-Lymphotropic Lentivirus;Feline T-Lymphotropic Virus;Food And Drug Administration;Food And Drug Administration (U.S.);Gene Products, Bacterial;Goals;Haart;Hiv;Hiv Infections;Hiv-1;Hiv-I;Hiv/Aids;Hiv/Aids Problem;Hiv1;Htlv-Iii;Htlv-Iii Infections;Htlv-Iii-Lav Infections;Hemato-Encephalic Barrier;Highly Active Antiretroviral Therapy;Hortega Cell;Human;Human Immunodeficiency Viruses;Human T-Cell Leukemia Virus Type Iii;Human T-Cell Lymphotropic Virus Type Iii;Human T-Lymphotropic Virus Type Iii;Human Immunodeficiency Virus 1;Human, General;Immunodeficiency Virus Type 1, Human;Immunodeficiency Virus, Feline;In Vitro;Incidence;Individual;Infection;Infiltration;Inflammatory Response;Investigational Drugs;Investigational New Drug Application;Investigational New Drugs;Knowledge;Lav-Htlv-Iii;Lps;Lead;Lipopolysaccharides;Lymphadenopathy-Associated Virus;Man (Taxonomy);Man, Modern;Marrow Monocyte;Microglia;Nerve Cells;Nerve Unit;Nervous System Diseases;Nervous System, Cns;Neural Cell;Neuraxis;Neurocyte;Neurologic;Neurologic Disorders;Neurological;Neurological Disorders;Neurons;Neurotoxins;Outcome;Pbmc;Pns Diseases;Pathology;Pb Element;Peripheral Blood Mononuclear Cell;Peripheral Nerve Diseases;Peripheral Nervous System Diseases;Peripheral Nervous System Disorders;Peripheral Neuropathy;Prevalence;Research Proposals;Source;Suicide;T-Cells;T-Lymphocyte;T-Lymphotropic Virus Type Iii Infections, Human;Therapeutic;Thymus-Dependent Lymphocytes;Time;Tissues;Toxic Effect;Toxicities;Toxin;Treatment Efficacy;Usfda;United States Food And Drug Administration;Viral;Viral Burden;Viral Diseases;Viral Gene Products;Viral Gene Proteins;Viral Load;Viral Load Result;Viral Proteins;Virus;Virus Diseases;Virus-Hiv;Viruses, General;Whblood;Whole Blood;Work;Abuse Of Drugs;Abuses Drugs;Anti-Retroviral;Anti-Retroviral Therapy, Highly Active;Antiretroviral;Antiretroviral Therapy;Base;Clinical Investigation;Commercialization;Cytokine;Disease/Disorder;Failure;Fatal Attempt;Fatal Suicide;Gitter Cell;Heavy Metal Pb;Heavy Metal Lead;Human T Cell Leukemia Virus Iii;Human T Lymphotropic Virus Iii;In Vitro Activity;In Vivo;Intent To Die;Macrophage;Mesoglia;Microglial Cell;Microgliocyte;Monocyte;Nervous System Disorder;Neuroaids;Neurological Disease;Neuronal;Neuropathology;Neuropsychological;Neurotoxicant;New Therapeutics;Next Generation Therapeutics;Novel;Novel Therapeutics;Perivascular Glial Cell;Pre-Clinical;Preclinical;Preclinical Safety;Preclinical Study;Public Health Relevance;Response;Self Recognition (Immune);Small Molecule;Suicidality;Therapeutic Efficacy;Therapeutically Effective;Thymus Derived Lymphocyte;Uptake;Viral Infection;Virus Infection;Virus Protein
