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HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism

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HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism This information is current as Todd Bradley, Guang Yang, Olga Ilkayeva, T. Matt Holl, of September 29, 2021. Ruijun Zhang, Jinsong Zhang, Sampa Santra, Christopher B. Fox, Steve G. Reed, Robert Parks, Cindy M. Bowman, Hilary Bouton-Verville, Laura L. Sutherland, Richard M. Scearce, Nathan Vandergrift, Thomas B. Kepler, M. Anthony Moody, Hua-Xin Liao, S. Munir Alam, Roger McLendon, Jeffrey I. Everitt, Christopher B. Newgard, Downloaded from Laurent Verkoczy, Garnett Kelsoe and Barton F. Haynes J Immunol 2016; 197:4663-4673; Prepublished online 14 November 2016; doi: 10.4049/jimmunol.1601484 http://www.jimmunol.org/content/197/12/4663 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/11/12/jimmunol.160148 Material 4.DCSupplemental References This article cites 67 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/197/12/4663.full#ref-list-1 by guest on September 29, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism Todd Bradley,*,†,1 Guang Yang,‡,1 Olga Ilkayeva,x,1 T. Matt Holl,‡ Ruijun Zhang,* Jinsong Zhang,* Sampa Santra,{ Christopher B. Fox,‖ Steve G. Reed,‖ Robert Parks,* Cindy M. Bowman,* Hilary Bouton-Verville,* Laura L. Sutherland,* Richard M. Scearce,* Nathan Vandergrift,*,† Thomas B. Kepler,# M. Anthony Moody,*,†† Hua-Xin Liao,* S. Munir Alam,*,† Roger McLendon,x Jeffrey I. Everitt,x Christopher B. Newgard,†† Laurent Verkoczy,*,†,x Garnett Kelsoe,*,‡ and Barton F. Haynes*,†,x The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross- Downloaded from reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb VHDJH and VLJL knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism. Thus, molecular mimicrybyHIV-1Envthatpromotestheevasionofhostanti–HIV-1Ab responses can be directed toward nonfunctional host protein epitopes that do not impair host protein function. Therefore, the 2F5 HIV Envgp41regionisakeyandsafetarget for HIV-1 vaccine development. The Journal of Immunology, 2016, 197: 4663–4673. http://www.jimmunol.org/ uman immunodeficiency virus–1 infection remains a seri- passive administration of bnAbs that target conserved Env epitopes ous threat to health worldwide, and developing an effec- (2F5, 4E10, 2G12, b12, VRC01, 3BNC117, or 10-1074) prevented H tive HIV-1 vaccine is a global priority. A major challenge simian HIV infection in monkeys (25–29). in achieving an effective vaccine is the inability of vaccines to Molecular mimicry of antigenic determinants between patho- induce broadly neutralizing Abs (bnAbs) that recognize conserved gens and host molecules can result in tissue damage, such as the epitopes on a majority of circulating HIV-1 strains (1–4). bnAbs Abs against a region of the hepatitis B virus that cross-react with have not been elicited by vaccination, yet up to 50% of individuals myelin basic protein and can lead to tissue damage in the CNS (30– by guest on September 29, 2021 chronically infected with HIV-1 develop bnAbs (5). Isolation of 32). Similarly, Campylobacter jejuni lipo-oligosaccharides mimic bnAbs from infected individuals revealed six conserved sites of host nervous system gangliosides and cause Guillain-Barre syn- vulnerability on the HIV-1 envelope protein (Env): the gp120 drome following infection (33, 34). Studies in mice demonstrated CD4 binding site (6–11), gp120 V1/V2 loop epitopes (12–14), that these host ganglioside Abs are under tolerance control (33). gp120 V3-glycan epitopes (15–17), the gp41 membrane-proximal Autoantibodies also were shown to penetrate the blood–brain external region (MPER) (18–21), the gp41 fusion domain (22), barrier and affect intracellular enzyme function of neuronal cells and the gp120–gp41 interface (23, 24). At high concentrations, during autoimmune disease (35). In retinopathy, anti-enolase Abs *Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710; assisted with rhesus macaque Ab gene sequencing; J.Z., H.B.-V., C.M.B., and L.V. †Department of Medicine, Duke University Medical Center, Durham, NC 27710; provided 2F5 knock-in mice and carried out immunization and tissue collection; S.S., ‡Department of Immunology, Duke University Medical Center, Durham, NC 27710; xDe- L.L.S., and R.M.S. assisted with rhesus macaque immunizations and sample collection; partment of Pathology, Duke University Medical Center, Durham, NC 27710; {Beth S.M.A., C.B.F., and S.G.R. provided membrane-proximal external region peptide- Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; ‖Infec- liposome immunogen; R.P. performed immunoassays; N.V. performed statistical anal- tious Disease Research Institute, Seattle, WA 98102; #Department of Microbiology, yses; T.B.K. designed software and performed analysis of Ab sequences; M.A.M. Boston University, Boston, MA 02215; **Department of Pediatrics, Duke University produced fluorophore-labeled membrane-proximal external region proteins and oversaw Medical Center, Durham, NC 27710; and ††Department of Pharmacology and Cancer flow cytometry experiments; R.M. and J.I.E. performed histopathology analysis; and Biology, Duke University Medical Center, Durham, NC 27710 B.F.H. designed the study, oversaw all experiments, analyzed all data, and wrote and edited the manuscript. 1T.B., G.Y., and O.I. contributed equally to this work. The sequences presented in this article have been submitted to GenBank (http://www. ORCIDs: 0000-0002-2342-8232 (R.Z.); 0000-0002-2195-2997 (J.Z.); 0000-0002- ncbi.nlm.nih.gov/geo/) under accession numbers KX914888–KX914899. 8796-1714 (S.S.); 0000-0002-6903-2831 (C.M.B.); 0000-0002-1383-6865 (T.B.K.); 0000-0002-3890-5855 (M.A.M.); 0000-0001-6682-4588 (R.M.); 0000-0003-0273- Address correspondence and reprint requests to Dr. Todd Bradley, Prof. Garnett 6284 (J.I.E.); 0000-0001-7497-6645 (L.V.). Kelsoe, and Prof. Barton F. Haynes, Human Vaccine Institute, Duke University Medical Center, 2 Genome Court, MSRBII, DUMC 103020, Durham, NC 27710. Received for publication August 25, 2016. Accepted for publication October 14, E-mail addresses: [email protected] (T.B.), [email protected] (G.K.), 2016. and [email protected] (B.F.H.) This work was supported by the Center for HIV/AIDS Vaccine Immunology- The online version of this article contains supplemental material. Immunogen Discovery (Grant UMI-AI100645), a grant from the National Institutes of Health/National Institute of Allergy and Infectious Diseases/Division of AIDS, Abbreviations used in this article: bnAb, broadly neutralizing Ab; CDRH3, third and a Collaboration for AIDS Vaccine Discovery Grant from the Bill & Melinda chain H complementarity region; dKI, double KI; ELDKWA, 2F5 core epitope; Gates Foundation. Env, envelope protein; GLA, glucopyranosyl lipid adjuvant; gl2F5, germline 2F5; KI, knock-in; KYNU, kynureninase; m2F5, mature 2F5; MPER, membrane-proximal T.B. isolated and characterized Abs, designed assays, analyzed and interpreted data, and external region; mutKYNU, mutant KYNU; RM, rhesus macaque. wrote and edited the manuscript; G.Y., T.M.H., and G.K. designed and analyzed the kynureninase in vitro enzyme assay, interpreted data, and edited the manuscript; O.I. Ó and C.B.N. performed tryptophan metabolite analysis; R.Z. and H.-X.L. designed and Copyright 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601484 4664 AUTOREACTIVE gp41 HIV-1 Abs DO NOT INHIBIT KYNU can alter the function of the enolase enzyme in neuronal cells (36). natants were purified by nickel and size-exclusion chromatography (55). 652 671 Furthermore, in multiple sclerosis, anti–heterogeneous nuclear ribo- Biotin-labeled SP62 ( QQEKNEQELLELDKWASLWN ) peptide and biotin-labeled MPER656 (656NEQELLELDKWASLWNWFNITNWLWYIK683) nucleoprotein Abs were found to traffic into neurons and lead to peptide were synthesized (CPC Scientific). apoptosis, contributing to multiple sclerosis pathology (37, 38). Recombinant and serum Ab binding was determined using ELISA, as HIV-1 bnAbs have unusual features, such as extensive somatic described (55, 56). hypermutation and long third H chain complementarity regions Mouse immunization (CDRH3s) that are associated with poly- or autoreactive BCRs, which can make Abs subject to immune tolerance control (39–41). We Mature 2F5 (m2F5) dKI and germline 2F5 (gl2F5) dKI mice were generated on the C57BL/6 background, as previously described (46, 50). Three groups demonstrated previously that many HIV-1 bnAbs are autoreactive and/ of four m2F5 dKI mice were immunized six times, every 14 d, with i.p. or polyreactive and the MPER-reactive bnAb, 2F5, binds to the tryp- injections (200 ml) of the MPER peptide-liposome (25 mg) formulated tophan metabolism enzyme kynureninase (KYNU) (42, 43).
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    Authors: Zheng Zhao, Delft University of Technology Marcel A. van den Broek, Delft University of Technology S. Aljoscha Wahl, Delft University of Technology Wilbert H. Heijne, DSM Biotechnology Center Roel A. Bovenberg, DSM Biotechnology Center Joseph J. Heijnen, Delft University of Technology An online version of this diagram is available at BioCyc.org. Biosynthetic pathways are positioned in the left of the cytoplasm, degradative pathways on the right, and reactions not assigned to any pathway are in the far right of the cytoplasm. Transporters and membrane proteins are shown on the membrane. Marco A. van den Berg, DSM Biotechnology Center Peter J.T. Verheijen, Delft University of Technology Periplasmic (where appropriate) and extracellular reactions and proteins may also be shown. Pathways are colored according to their cellular function. PchrCyc: Penicillium rubens Wisconsin 54-1255 Cellular Overview Connections between pathways are omitted for legibility. Liang Wu, DSM Biotechnology Center Walter M. van Gulik, Delft University of Technology L-quinate phosphate a sugar a sugar a sugar a sugar multidrug multidrug a dicarboxylate phosphate a proteinogenic 2+ 2+ + met met nicotinate Mg Mg a cation a cation K + L-fucose L-fucose L-quinate L-quinate L-quinate ammonium UDP ammonium ammonium H O pro met amino acid a sugar a sugar a sugar a sugar a sugar a sugar a sugar a sugar a sugar a sugar a sugar K oxaloacetate L-carnitine L-carnitine L-carnitine 2 phosphate quinic acid brain-specific hypothetical hypothetical hypothetical hypothetical
  • KYNURENINE Forjlahlidase in MUTANTS of DROSOPHILA' Workers Have Shown That the Brown Eye Pigment of Drosophila Melano

    KYNURENINE Forjlahlidase in MUTANTS of DROSOPHILA' Workers Have Shown That the Brown Eye Pigment of Drosophila Melano

    KYNURENINE FORJlAhlIDASE IN MUTANTS OF DROSOPHILA’ EDWARD GLASSMAN2* Merganthder Laboratory for Biology, The Johns Hopkins University, Baltimore, Maryland Received January 30, 1956 workers have shown that the brown eye pigment of Drosophila melano- MANYgaster is a derivative of tryptophan, and that gene mutations affecting the conversion of tryptophan to kynurenine (the v+ substance) in Drosophila manifest themselves as deficiencies in this pigment (cf. EPHRUSSI1942 ; GREEN1949; KIKKAWA 1950a). Recent examination of the enzymes responsible for this conversion in mam- malian liver has indicated that these reactions involve a peroxidation of tryptophan to N’-formylkynurenine (KNOXand ~IEHLER1950), and the hydrolysis of the latter compound to kynurenine and formic acid (MEHLERand KNOX1950). The enzyme for this hydrolysis, kynurenine formamidase (JAKOBY 1954), is apparently specific for formylated aromatic amines and is able to hydrolyze formylanthranilic acid, formylorthanilic acid, formylnitroaniline, and others, although at a much slower rate than it acts upon formylkynurenine. This enzyme is quite active in cell-free extracts of Drosophila, and some of its properties will be described below. Un- fortunately it has not been possible to demonstrate the peroxidation of tryptophan to formylkynurenine in cell-free extracts (assayed by tryptophan disappearance) even though larvae, pupae, and adults have been examined in various ways. Kynurenine formamidase was assayed in various strains in which the production of kynurenine is known to be altered. These included the vermilion mutants, in which the formation of kynurenine is blocked completely, and ruby, claret, and others, in which the amount is merely lessened (BEADLEand EPHRUSSI1937). In order to determine the differences between strains, a variety of other strains in which ky- nurenine production is normal was also examined.