Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

• Published in: Gene therapy Vol. 9; no. 13; pp. 889 - 897
• Main Authors: SCHROERS, R, DAVIS, C. M, WAGNER, H-J, CHEN, S-Y
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.07.2002
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Applied cell therapy and gene therapy; Biological and medical sciences; Biotechnology; CD28 antigen; CD3 antigen; CD3 Complex - analysis; CD4 Antigens - analysis; Cell culture; Cell surface; Cells, Cultured; Chemokine CCL5 - genetics; Chemokine receptors; DNA, Viral - analysis; Erythrocytes - virology; Expression vectors; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gene therapy; Gene transfer; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Health. Pharmaceutical industry; HIV; HIV Infections - therapy; HIV-1 - genetics; Human immunodeficiency virus; Humans; Industrial applications and implications. Economical aspects; Infections; Lentivirus - genetics; Lymphocytes; Lymphocytes T; Medical sciences; Polymerase Chain Reaction - methods; RANTES; Receptors, CCR1; Receptors, CCR3; Receptors, CCR5 - analysis; Receptors, Chemokine - analysis; Receptors, CXCR4 - analysis; T-Lymphocytes - chemistry; T-Lymphocytes - immunology; Transduction, Genetic - methods; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Viruses; Human; HIV-1 virus; RANTES; Retroviridae; Activation; Lentivirus; Genetic transfer; Virus; Cell line; T-Lymphocyte; Human immunodeficiency virus; Gene therapy; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3301711

Intrakines, modified intracellular chemokines, offer a novel strategy to prevent cellular entry of HIV-1 by blocking the surface expression of HIV-1 co-receptors. To investigate potential clinical applications of the RANTES-intrakine, we explored the use of HIV-1-based lentiviral vectors for therapeutic gene transfer into T-lymphocytes. RANTES-intrakine genes can be efficiently transduced into primary human T-lymphocytes by lentiviral vectors, especially when human T-lymphocytes were stimulated with CD3 and CD28 antibodies. The transduced T cells showed decreased surface expression of the chemokine receptor CCR-5, as well as CCR-1 and CCR-3. This lentivirus-mediated approach to intrakine gene transfer protected human T-lymphocytes from infection by a variety of R5-tropic HIV-1 strains. A quantitative real-time PCR assay, developed to monitor cells for HIV entry and persistence, revealed persistent low copy numbers of proviral HIV DNA in RANTES intrakine-transduced T-lymphocytes during 3-week culture, suggesting that viruses produced from infected untransduced cell populations were unable to infect the surrounding transduced T-lymphocytes. We conclude that targeting HIV-1 co-receptors to block virus entry with lentiviral vectors is an attractive approach to the control of HIV-1 infection.