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Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors

Gene Therapy volume 15, pages 1079–1089 (2008)Cite this article

Abstract

The host factor α isoform of the tripartite motif 5 (TRIM5α) restricts human immunodeficiency virus type 1 (HIV-1) infection in certain non-human primate species. Restriction of HIV-1 is enhanced by binding of the viral capsid to cyclophilin A (CypA) in target cells, although CypA is not absolutely required for restriction in rhesus macaque cells. Simian immunodeficiency virus (SIV) is not restricted by rhesus macaque TRIM5α and its capsid does not bind to CypA. Here, the effect of lentiviral CypA dependence on restriction in different tissues was examined by engineering an HIV-1 capsid quadruple mutant (V86P/H87Q/I91V/M96I) lentiviral vector (HIVquad) that is CypA-independent. Whereas HIV-1 was restricted in rhesus macaque and owl monkey epithelial cells, infection with the HIVquad vector was efficient at high viral concentrations. In contrast, HIVquad was largely restricted in primary rhesus macaque CD34+ cells. Human epithelial and primary CD34+ cells were permissive for HIV-1, HIVquad and SIV, whereas transduction of human T cells by HIVquad or SIV was impaired. The restrictive human cells did not express increased levels of TRIM5α, and restriction was not relieved by abolishing CypA, consistent with HIVquad and SIV being CypA-independent. Pseudotyping of lentiviral vectors with the gibbon ape leukemia virus envelope altered their sensitivity to perturbations of the virus–CypA interaction compared to pseudotyping with vesicular stomatitis virus glycoproteins, suggesting that the viral entry pathway modulates restriction. Together, these studies reveal that an HIV-1 capsid quadruple mutant can partially overcome lentiviral restriction in non-human primate epithelial cells, but not in hematopoietic cells. Similarly, human cells vary in their permissiveness for CypA-independent lentiviruses, and suggest the presence of tissue-specific factor(s) that can inhibit lentiviral transduction independently of viral interaction with TRIM5α and CypA.

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Acknowledgements

We thank Paul Bieniasz for providing the pLNCX-TRIM5αRhe plasmid and Arthur Nienhuis for supplying the SIVmac1A11-derived vector plasmids. These studies were supported by NIH Grants AI52798 (DBK) and HL069748 (AFT) and the Primate Center base operating grant RR00169.

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Authors and Affiliations

  1. Division of Research Immunology/Bone Marrow Transplantation, The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA, USA

    C A Kahl, P M Cannon, J Oldenburg & D B Kohn

  2. Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    P M Cannon & D B Kohn

  3. Department of Biochemistry, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    P M Cannon

  4. California National Primate Research Center, University of California, Davis, CA, USA

    A F Tarantal

  5. Departments of Pediatrics and Cell Biology and Human Anatomy, University of California, Davis, CA, USA

    A F Tarantal

  6. Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, University of California, Davis, CA, USA

    A F Tarantal

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  1. C A Kahl
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Correspondence to D B Kohn.

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Kahl, C., Cannon, P., Oldenburg, J. et al. Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors. Gene Ther 15, 1079–1089 (2008). https://doi.org/10.1038/gt.2008.50

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  • DOI: https://doi.org/10.1038/gt.2008.50

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