title: Cell-Delivered Entry Inhibitors for HIV-1: CCR5 Downregulation and Blocking Virus/Membrane Fusion in Defending the Host Cell Population.
abstract: HIV-1 infection requires the presence of the CD4 receptor on the target cell surface and a coreceptor, predominantly CC-chemokine receptor 5 (CCR5). It has been shown that individuals who are homozygous for a defective CCR5 gene are protected from HIV-1 infection. A novel self-inactivating lentiviral vector LVsh5/C46 (Cal-1) has been engineered to block HIV-1 infection with two viral entry inhibitors, conferring resistance to HIV-1 infection from both CCR5 and CXCR4 tropic strains. Cal-1 encodes a short hairpin RNA (sh5) to downregulate CCR5 and C46, an HIV-1 fusion inhibitor. Gene therapy by Cal-1 is aimed at transducing CD4+T cells and CD34+hematopoietic stem/progenitor cells in an autologous transplant setting. Pre-clinical safety and efficacy studies in vitro and in vivo (humanized mouse model and nonhuman primates) have shown that Cal-1 is safe with no indication of any toxicity risk and acts to decrease viral load and increase CD4 counts. Two clinical trials are underway using Cal-1: a phase I/II study to assess safety and feasibility in an adult HIV-1-positive population not on antiretroviral therapy (ART); and a second Fred Hutchinson Investigator Initiated phase I study to assess safety and feasibility in adults with HIV-1-associated non-Hodgkin or Hodgkin lymphoma.
authors.affiliation: 1 Calimmune, Inc. , Tucson, Arizona.
authors.forename: Geoff
authors.initials: G
authors.lastname: Symonds
authors.affiliation: 1 Calimmune, Inc. , Tucson, Arizona.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bartlett
authors.affiliation: 2 Fred Hutchinson Cancer Research Center , Seattle, Washington.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
authors.affiliation: 1 Calimmune, Inc. , Tucson, Arizona.
authors.forename: Marlene
authors.initials: M
authors.lastname: Tsie
authors.affiliation: 1 Calimmune, Inc. , Tucson, Arizona.
authors.forename: Louis
authors.initials: L
authors.lastname: Breton
mesh_terms: D000328:Adult; D000818:Animals; D001691:Biological Therapy / Q000379:methods; D065100:CCR5 Receptor Antagonists; D018791:CD4 Lymphocyte Count; D002986:Clinical Trials as Topic; D015536:Down-Regulation; D015316:Genetic Therapy / Q000379:methods*; D015658:HIV Infections / Q000235:genetics / Q000628:therapy* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells; D006801:Humans; D008561:Membrane Fusion; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019718:Receptors, CXCR4; D015728:Receptors, HIV / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics; D019562:Viral Load
chemical_list: C515020:C46 HIV-1 fusion inhibitory peptide; D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D011993:Recombinant Fusion Proteins
keywords: CCR5; CD34; CD4; CXCR4; Cal-1; HIV-1; T cell; gene therapy; lentiviral vector; stem cell