PMID:9570571
| Citation |
Zhou, P, Goldstein, S, Devadas, K, Tewari, D and Notkins, AL (1998) Cells transfected with a non-neutralizing antibody gene are resistant to HIV infection: targeting the endoplasmic reticulum and trans-Golgi network. J. Immunol. 160:1489-96 |
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| Abstract |
Plasmids containing single chain Fv (scFv) non-neutralizing human anti-HIV-1 gp41 Ab cDNA, with or without endoplasmic reticulum (ER) or trans-Golgi network (TGN) retention signals, were constructed. Stable transfectants expressing these scFvs then were generated from COS-7 cells and HIV-1-susceptible CD4+ human T cells (Jurkat). scFv without a retention signal was secreted from cells, whereas scFv with an ER or TGN retention signal remained primarily within targeted intracellular compartments. The expression of scFv, scFv-ER, and scFv-TGN did not adversely affect the appearance of uninfected cells, as measured by growth rate or CD4 expression. Pulse-chase experiments revealed that the t(1/2) of scFv-ER and scFv-TGN within cells was greater than 24 h and less than 9 h, respectively. The scFv-ER and scFv-TGN bound HIV gp160, and the scFv-ER-gp160 and the scFv-TGN-gp160 complexes were stable within HIV-infected transfectants. Further studies revealed that the maturation processing of gp160 into gp120 and gp41 was blocked in the scFv-ER transfectants, but not in the scFv-TGN transfectants. Moreover, HIV replication, as measured by p24, was inhibited by up to 99% in cells transfected with scFv-ER or scFv-TGN, but was not inhibited in cells transfected with the secretory form of scFv. It is concluded that the targeting of non-neutralizing anti-HIV-1 Abs to specific intracellular compartments blocks HIV replication and represents a potential therapeutic strategy for protecting uninfected lymphopoietic stem cells from HIV-1-infected patients. |
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| Keywords |
Animals; Antibodies, Viral/biosynthesis; Antibodies, Viral/genetics; Antiviral Agents/pharmacology; CD4-Positive T-Lymphocytes/immunology; CD4-Positive T-Lymphocytes/virology; Endoplasmic Reticulum/immunology; Endoplasmic Reticulum/metabolism; Gene Products, env/metabolism; Giant Cells/immunology; Giant Cells/virology; Golgi Apparatus/immunology; Golgi Apparatus/metabolism; HIV Envelope Protein gp160/immunology; HIV Infections/immunology; HIV Infections/virology; HIV-1/immunology; HIV-1/metabolism; HIV-1/physiology; Humans; Immunity, Innate; Immunoglobulin Fragments/biosynthesis; Immunoglobulin Fragments/genetics; Immunoglobulin Fragments/pharmacology; Immunoglobulin Variable Region/biosynthesis; Immunoglobulin Variable Region/genetics; Immunoglobulin Variable Region/pharmacology; Intracellular Fluid/immunology; Intracellular Fluid/metabolism; Jurkat Cells; Neutralization Tests; Precipitin Tests; Rats; Transfection/genetics; Transfection/immunology; Virus Replication/genetics; Virus Replication/immunology |
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