Document text
Principal Investigator: Kenneth W Witwer
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2019
Award: $457,682
Funding agency: National Institute on Drug Abuse
DESCRIPTION (provided by applicant): Combined antiretroviral therapy (cART) has dramatically changed the HIV epidemic, prolonging life and reducing morbidities. Nevertheless, a wide range of non-AIDS conditions continue to afflict people living with HIV, including cancers as well as cardiovascular, neurologic, kidney and bone diseases. These conditions are caused or influenced by inflammation states and immune activation and dysfunction that persist despite successful cART. In some cases, these conditions may be exacerbated by substance abuse, for example, cigarette smoking, which is more prevalent amongst HIV-infected individuals than in the general population. Extracellular vesicles (EV), including "exosomes" that bud into endosomal compartments, are membrane particles release by all known cell types that engage in intercellular communication. EV contribute to disease pathogenesis and are actively investigated, especially in cancers, as biomarkers and potential therapeutic platforms. Unfortunately, there is a relative dearth of information on the role of EV in HIV infection and substance abuse. To address this need in HIV and cigarette abuse, we have assembled an outstanding international team with combined strengths in HIV, EV, and immunology research, and technical portfolios ranging from EV isolation, nanoparticle characterization, and EV functional assays to bioinformatics, proteomics, lipidomics, and RNomics. Our investigators have identified a plasma signature of acute retroviral infection; characterized the roles of cellulr proteins in exosome and HIV release; unraveled the immunomodulatory function of EV; and confirmed effects of cigarettes on the immune system. Here, we will identify cellular proteins differentially involved in HIV and EV release (Aim 1), then use these findings and other methods to characterize "omics" changes to CD4+ T cell and macrophage exosomes and EV that occur with HIV infection or exposure to components of cigarette smoke (Aim 2). Functional studies will demonstrate how CD4+ T cell and macrophage EV released in HIV infection and nicotine abuse affect the qualities and function of cells that contribute to innate and adaptive immune responses (Aim 3). Finally, quantity, compositional quality, and function of circulating EV will be
assessed in smoking and nonsmoking individuals who are diagnosed with HIV, both before and after they begin cART (Aim 4). The goal of these studies is to define the role played by exosomes/EVs in the promotion of pro-inflammatory states in HIV-1 infected individuals and smokers. Our findings will provide important insights into the pathogenesis of immune dysfunction/inflammation observed in these populations. We expect that our results will open pathways to new, likely EV-based, therapeutic interventions, helping to solve one of the major clinical challenges in HIV-1 medicine: the lack of treatments to limit immune activation and inflammation in HIV+ persons treated with cART.
Terms: <AIDS><AIDS Virus><AIDS drugs><ATGN><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Acute><Address><Affect><Anti-AIDS Agents><Anti-AIDS Drugs><Anti-HIV Agents><Anti-HIV Drugs><Anti-Human Immunodeficiency Virus Agents><Antigens><Area><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bio-Informatics><Bioassay><Biogenesis><Bioinformatics><Biologic Assays><Biological Assay><Biological Markers><Blood Plasma><Blood monocyte><Bone Diseases><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancers><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Function><Cell Line><Cell Process><Cell Signaling><Cell membrane><Cell physiology><Cell to Cell Communication and Signaling><Cell-Cell Signaling><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Characteristics><Cigarette><Clinical><Communication><Cytoplasmic Membrane><Cytosol><Death><Development><Diagnosis><Disease><Disorder><Epidemic><Exposure to><General Population><General Public><General Viruses><Goals><HIV><HIV Infections><HIV-1><HIV-I><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Health><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immune system><Immunes><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunology><Immunomodulation><Impairment><Individual><Infection><Inflammation><Inflammatory><International><Intracellular Communication and Signaling><Intracellular Membranes><Investigation><Investigators><Kidney Diseases><LAV-HTLV-III><Life><Lipid Bilayers><Lipids><Lymphadenopathy-Associated Virus><Malignant Neoplasms><Malignant Tumor><Marrow monocyte><Mediating><Medicine><Membrane><Methods><Modification><Molecular><Morbidity><Morbidity - disease rate><NSF attachment protein receptor><Nephropathy><Nervous System Diseases><Neurologic Disorders><Neurological Disorders><Nicotine><Non-Polyadenylated RNA><Nucleic Acids><Origin of Life><Pathogenesis><Pathway interactions><Patients><Persons><Plasma><Plasma Membrane><Plasma Serum><Play><Population><Process><Property><Proteins><Proteomics><RNA><RNA Gene Products><Renal Disease><Research><Research Personnel><Researchers><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><Role><SNAP receptor><SNARE><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Site><Smoker><Smoking><Strains Cell Lines><Structure><Subcellular Process><Substance abuse problem><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Techniques><Therapeutic><Therapeutic Intervention><Validation><Virion><Virus><Virus Particle><Virus Replication><Virus-HIV><abuse of substances><adaptive immune response><allergic/immunologic body system><allergic/immunologic organ system><anti-retroviral therapy><anti-retroviral treatment><antiAIDS agent><antiretroviral therapy><antiretroviral treatment><base><bio-markers><biologic marker><biological signal transduction><biomarker><bone disorder><cardiovascular disorder><cell type><cigarette smoke><cigarette smoke exposure><cigarette smoking><cigarette use><cultured cell line><developmental><exosome><experience><exposure to cigarette smoke><exposure to nicotine><extracellular vesicles><genome editing><genomic editing><host response><immune activation><immune modulation><immune regulation><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><insight><intercellular communication><interest><intervention therapy><kidney disorder><lipid bilayer membrane><macrophage><malignancy><membrane structure><monocyte><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><nervous system disorder><neurological disease><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><nicotine abuse><nicotine exposure><non-smoker><non-smoking><nonsmoker><nonsmoking><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><particle><pathway><plasmalemma><prevent><preventing><public health relevance><renal disorder><response><social role><soluble N-ethylmaleimide-sensitive-factor attachment protein receptor><substance abuse><vesicle release><vesicular release><viral multiplication><viral replication><virus multiplication>