Document text
Principal Investigator: Florian Hladik
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2019
Award: $502,606
Funding agency: National Institute on Drug Abuse
DESCRIPTION (provided by applicant): We have recently shown that human semen contains trillions of extracellular vesicles (SEV) carrying small extracellular RNA (exRNA) molecules that may regulate the immune system (Nucleic Acids Research, 42:7290-7304, 2014). In unpublished studies, we have found that SEV suppress adaptive T cell responses, most likely by affecting antigen presentation. SEV also associate with HIV virions in vitro and in our hands enhance HIV susceptibility, although another group recently reported the opposite. Ultimately, SEV likely impact HIV infection, both by directly interacting with HIV and its target cells, and by
compromising protective T cell immunity against HIV. Opioids too affect the immune system, although the exact mechanisms and functional outcomes are not well- understood. Heroin abuse leads to an immunocompromised state and increases HIV susceptibility, but the behavioral and biological causes for this are difficult to untangle. Heroin addiction is often treated with long- term methadone or buprenorphine medication, two opioids whose immunological properties and effects on HIV infection also remain unclear. Thus, the interplay of extracellular vesicles in semen and opioid use may have important consequences for HIV infection and the immune system, and this proposal will investigate these connections. We will determine the effects of SEV on HIV infection in a vaginal explant model and dissect the nature and extent of SEV- mediated inhibition of adaptive T cell responses, including to HIV vaccination. We will perform comparative studies of HIV susceptibility, adaptive T cell responses and SEV biology (exRNA composition and function) in blood and semen samples from normal donors, as well as heroin users before and three months after starting assisted methadone or buprenorphine treatment. The three opioids will also be tested in culture, because expression of the Opioid Receptor-Like 1 receptor on vaginal leukocytes (our data), and reports of other non- opioid receptors such as Toll-like receptor 4, indicate that opioids could directly affect leukocyt biology. SEV and opioid interactions will be addressed in combinatorial experiments. These studies will deepen our understanding of how opioids and extracellular vesicles in semen, alone or in conjunction, impact sexual HIV transmission. Knowledge of these effects will help to improve HIV vaccination outcomes, focus other HIV prevention strategies, and provide new information on the clinical benefits of methadone versus buprenorphine substitution therapy.
Terms: <A vaginae><A. vaginae><A.vaginae><AIDS Virus><AIDS prevention><ATGN><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adanon><Address><Affect><Althose><Antigen Presentation><Antigen-Presenting Cells><Antigens><Atopobium vaginae><Behavioral><Biological><Biology><Blood><Blood Reticuloendothelial System><Blood leukocyte><Bunavail><Buprenorphine><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD195 Antigen><CD195 Antigen Gene><CHEMR13><CHEMR13 Gene><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><CXC-R4><CXCR-4><CXCR4><CXCR4 gene><Cell Body><Cells><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Clinical><Comparative Study><Consequences of HIV><D2S201E><Data><Data Reporting><Dendritic 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Effect><Immunosuppressive Agents><Immunosuppressive Effect><Impairment><In Vitro><Individual><Infection><Knowledge><LAP3><LAV-HTLV-III><LCR1><LESTR><Langerhans cell><Leukocytes><Leukocytes Reticuloendothelial System><Link><Liposomal><Liposomes><Literature><Lymphadenopathy-Associated Virus><Macaca mulatta><Marrow leukocyte><Measures><Mediating><Medication><Messenger RNA><Methadone><Methadose><Modeling><Modern Man><Mucosa><Mucosal Tissue><Mucous Membrane><NPY3R><NPYR><NPYRL><NPYY3R><Nature><Non-Polyadenylated RNA><Nonnarcotic Analgesics><Nonopioid Analgesics><Nucleic Acids><Opiate Addiction><Opiate Dependence><Opiate Receptors><Opiate user><Opiates><Opioid><Opioid Receptor><Opioid drug user><Opioid user><Outcome><PBMC><Peripheral Blood Mononuclear Cell><Pharmaceutic Preparations><Pharmaceutical Preparations><Predisposition><Preventative strategy><Prevention strategy><Preventive strategy><Property><Psyche structure><RNA><RNA Gene Products><RNA Sequences><RNA Transport><Receptor Protein><Reporting><Research><Rhesus><Rhesus Macaque><Rhesus Monkey><Ribonucleic Acid><Ribonucleic Acid Transport><Risk><SIV><Sampling><Semen><Seminal fluid><Simian Immunodeficiency Viruses><Suboxone><Susceptibility><System><T cell response><T-Cells><T-Lymphocyte><TLR4><TLR4 gene><Testing><Time><Toll Homologue><Transmission><Vaccinated><Vaccination><Vaccine Antigen><Vagina><Vaginal><Veiled Cells><Virion><Virus><Virus Particle><Virus-HIV><White Blood Cells><White Cell><Zubsolv><accessory cell><adaptive immunity><allergic/immunologic body system><allergic/immunologic organ system><antigen-specific T cells><base><buprenorphine + naloxone><buprenorphine and naloxone><buprenorphine treatment><buprenorphine with naloxone><buprenorphine-naloxone><buprenorphine/naloxone><combinatorial><data representation><drug/agent><experience><experiment><experimental research><experimental study><extracellular><extracellular vesicles><fighting><functional outcomes><heroin intake><heroin use><host response><human immunodeficiency virus vaccine><immune modulation><immune regulation><immune suppression><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressed patient><immunosuppressive><improved><in vivo><insight><intraepithelial><mRNA><medication-assisted treatment><mental><methadone maintenance><methadone maintenance program><methadone maintenance therapy><methadone maintenance treatment><methadone treatment><non-drug><non-narcotic analgesic><non-opiate analgesic><non-opioid><non-opioid analgesic><nondrug><nonopiate analgesic><nonopioid><opiate consumption><opiate drug use><opiate intake><opiate use><opioid addiction><opioid consumption><opioid dependence><opioid dependent><opioid drug use><opioid intake><opioid use><particle><public health relevance><receptor><response><sexual HIV transmission><thymus derived lymphocyte><toll-like receptor 4><transmission process><vagina infection><vaginal infection><white blood cell><white blood corpuscle>