ALBERT

Beschreibung: Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) 〉 5 mug ml(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC50) 〈 0.05 mug ml(-1)). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17-77 mug ml(-1) of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352131/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352131/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gardner, Matthew R -- Kattenhorn, Lisa M -- Kondur, Hema R -- von Schaewen, Markus -- Dorfman, Tatyana -- Chiang, Jessica J -- Haworth, Kevin G -- Decker, Julie M -- Alpert, Michael D -- Bailey, Charles C -- Neale, Ernest S Jr -- Fellinger, Christoph H -- Joshi, Vinita R -- Fuchs, Sebastian P -- Martinez-Navio, Jose M -- Quinlan, Brian D -- Yao, Annie Y -- Mouquet, Hugo -- Gorman, Jason -- Zhang, Baoshan -- Poignard, Pascal -- Nussenzweig, Michel C -- Burton, Dennis R -- Kwong, Peter D -- Piatak, Michael Jr -- Lifson, Jeffrey D -- Gao, Guangping -- Desrosiers, Ronald C -- Evans, David T -- Hahn, Beatrice H -- Ploss, Alexander -- Cannon, Paula M -- Seaman, Michael S -- Farzan, Michael -- HHSN261200800001E/PHS HHS/ -- P01 AI100263/AI/NIAID NIH HHS/ -- P30 AI045008/AI/NIAID NIH HHS/ -- R01 AI058715/AI/NIAID NIH HHS/ -- R01 AI080324/AI/NIAID NIH HHS/ -- R01 AI091476/AI/NIAID NIH HHS/ -- R01 AI095098/AI/NIAID NIH HHS/ -- R01 AI098485/AI/NIAID NIH HHS/ -- RR000168/RR/NCRR NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Mar 5;519(7541):87-91. doi: 10.1038/nature14264. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA. ; Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA. ; Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA. ; Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA. ; Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA [2] Immunathon Inc., Cambridge, Massachusetts 02141, USA. ; Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. ; 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Department of Immunology, Institut Pasteur, Paris, 75015, France. ; Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Immunology and Microbial Science, IAVI Neutralizing Antibody Center, and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Howard Hughes Medical Institute, New York, New York 10065, USA. ; 1] Department of Immunology and Microbial Science, IAVI Neutralizing Antibody Center, and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA. ; AIDS and Cancer Virus Program, Leidos Biomedical Research, Incorporated, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. ; 1] Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA [2] Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. ; Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53711, USA. ; Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707797" target="_blank"〉PubMed〈/a〉

Beschreibung: Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720389/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720389/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Durst, Ronen -- Sauls, Kimberly -- Peal, David S -- deVlaming, Annemarieke -- Toomer, Katelynn -- Leyne, Maire -- Salani, Monica -- Talkowski, Michael E -- Brand, Harrison -- Perrocheau, Maelle -- Simpson, Charles -- Jett, Christopher -- Stone, Matthew R -- Charles, Florie -- Chiang, Colby -- Lynch, Stacey N -- Bouatia-Naji, Nabila -- Delling, Francesca N -- Freed, Lisa A -- Tribouilloy, Christophe -- Le Tourneau, Thierry -- LeMarec, Herve -- Fernandez-Friera, Leticia -- Solis, Jorge -- Trujillano, Daniel -- Ossowski, Stephan -- Estivill, Xavier -- Dina, Christian -- Bruneval, Patrick -- Chester, Adrian -- Schott, Jean-Jacques -- Irvine, Kenneth D -- Mao, Yaopan -- Wessels, Andy -- Motiwala, Tahirali -- Puceat, Michel -- Tsukasaki, Yoshikazu -- Menick, Donald R -- Kasiganesan, Harinath -- Nie, Xingju -- Broome, Ann-Marie -- Williams, Katherine -- Johnson, Amanda -- Markwald, Roger R -- Jeunemaitre, Xavier -- Hagege, Albert -- Levine, Robert A -- Milan, David J -- Norris, Russell A -- Slaugenhaupt, Susan A -- 1P30 GM103342/GM/NIGMS NIH HHS/ -- 8P20 GM103444-07/GM/NIGMS NIH HHS/ -- C06 RR018823/RR/NCRR NIH HHS/ -- I01 BX002327/BX/BLRD VA/ -- K24 HL67434/HL/NHLBI NIH HHS/ -- R00-MH095867/MH/NIMH NIH HHS/ -- R01 HL109004/HL/NHLBI NIH HHS/ -- R01 HL127692/HL/NHLBI NIH HHS/ -- R01-HL095696/HL/NHLBI NIH HHS/ -- R01-HL109004/HL/NHLBI NIH HHS/ -- R01-HL127692/HL/NHLBI NIH HHS/ -- R01-HL33756/HL/NHLBI NIH HHS/ -- R01HL109506/HL/NHLBI NIH HHS/ -- R01HL122906-01/HL/NHLBI NIH HHS/ -- R01HL72265/HL/NHLBI NIH HHS/ -- T32 HL007208/HL/NHLBI NIH HHS/ -- T32 HL007260/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 3;525(7567):109-13. doi: 10.1038/nature14670. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA. ; Cardiology Division, Hadassah Hebrew University Medical Center, POB 12000 Jerusalem, Israel. ; Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA. ; Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA. ; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France. ; Universite Paris Descartes, Sorbonne Paris Cite, Faculty of Medicine, 75006 Paris, France. ; Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Yale-New Haven Hospital Heart and Vascular Center, Yale School of Medicine, 20 York Street, New Haven, Connecticut 06510, USA. ; Department of Cardiology, University Hospital Amiens; INSERM U-1088, Jules Verne University of Picardie, 80000 Amiens, France. ; Inserm U1087; Institut du Thorax; University Hospital, 44007 Nantes, France. ; Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), 28029 Madrid, Spain. ; Hospital Universitario Monteprincipe, 28660 Madrid, Spain. ; Genetic Causes of Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain. ; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Catalonia, Spain. ; Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Catalonia, Spain. ; CIBER in Epidemiology and Public Health (CIBERESP), 08036 Barcelona, Catalonia, Spain. ; Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain. ; CNRS, UMR 6291, 44007 Nantes, France. ; Universite de Nantes, 44322 Nantes, France. ; CHU Nantes, l'Institut du Thorax, Service de Cardiologie, 44093 Nantes, France. ; Service d'Anatomie Pathologique, Hopital Europeen Georges Pompidou, 75015 Paris, France. ; National Heart and Lung Institute, Harefield, Heart Science Centre, Imperial College London, London SW7 2AZ, UK. ; Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, USA. ; INSERM UMR_S910, Team physiopathology of cardiac development Aix-Marseille University, Medical School La Timone, 13885 Marseille, France. ; Department of Cellular and Molecular Biology, University of Texas Health Science Center Northeast Tyler, Texas75708, USA. ; Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA. ; Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. ; Assistance Publique - Hopitaux de Paris, Departement de Genetique, Hopital Europeen Georges Pompidou, 75015 Paris, France. ; Assistance Publique - Hopitaux de Paris, Departement de Cardiologie, Hopital Europeen Georges Pompidou, 75015 Paris, France. ; Cardiac Ultrasound Laboratory, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258302" target="_blank"〉PubMed〈/a〉