Suppression of HIV-1 infection in primary CD4 T cells transduced with a self-inactivating lentiviral vector encoding a membrane expressed gp41-derived fusion inhibitor.
Peptidomimetics of HIV-1 gp41 sequences required for membrane fusion are potent inhibitors of HIV-1 entry. We hypothesize that expression of a membrane-bound gp41-derived fusion inhibitor will confer HIV-1 resistance to primary CD4 T cells. Efficient gene delivery and stable expression of a membrane-bound gp41-derived fusion inhibitor to primary CD4 T cells was accomplished using a self-inactivating lentiviral vector. A potent antiviral effect was observed when transduced CD4 T cells were challenged with a highly virulent CXCR4-tropic strain of HIV-1. Production of soluble p24 in the supernatant was inhibited 100-fold, and cytopathic effects were evident early in non-transduced cells and absent in transduced cells. Expression of the gp41 sequences was not detrimental to CD4 cells as transduced CD4 T cells exhibited a population doubling time that was equivalent to T cells transduced with a control vector. Results from this study support the rationale to use this lentiviral vector targeted at HIV entry as a potential gene therapy for HIV infection.
Perez
E E
EE
Children's Hospital of Philadelphia, Division of Allergy and Immunology, Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Riley
J L
JL
Carroll
R G
RG
von Laer
D
D
June
C H
CH
D019380:Anti-HIV Agents / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D016655:HIV Core Protein p24 / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000276:immunology; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage; D015658:HIV Infections / Q000276:immunology / Q000628:therapy*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D016086:Lentivirus / Q000235:genetics* / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology; D014161:Transduction, Genetic
D019380:Anti-HIV Agents; D016655:HIV Core Protein p24; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D019718:Receptors, CXCR4