Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components
| Autor: | Jeremy Luban, Gladys Martinetti, Patrick Ziegler, Martha R. Neagu, Christian Grütter, Thomas Pertel, Luca Mazzucchelli, Markus G. Manz, Caterina Strambio-De-Castillia, Markus G. Grütter |
|---|---|
| Přispěvatelé: | University of Zurich, Luban, J |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
CD4-Positive T-Lymphocytes
Models Molecular Adoptive cell transfer Protein Conformation Genetic enhancement Cypa 2700 General Medicine Protein Engineering Antiviral Restriction Factors Tripartite Motif Proteins Mice 0302 clinical medicine Carrier Proteins/genetics/*metabolism ddc:616 Mice Knockout 0303 health sciences biology virus diseases General Medicine Adoptive Transfer 3. Good health Cell biology DNA-Binding Proteins Cyclophilin A/genetics/*metabolism medicine.anatomical_structure TRIM5alpha Aotidae Cyclophilin A HIV-1/*metabolism Research Article Anti-HIV Agents Recombinant Fusion Proteins Ubiquitin-Protein Ligases T cell Molecular Sequence Data 610 Medicine & health Cell Line 03 medical and health sciences 10019 Department of Biochemistry medicine Animals Humans Amino Acid Sequence 030304 developmental biology CD4-Positive T-Lymphocytes/cytology/immunology biology.organism_classification Virology Fusion protein Recombinant Fusion Proteins/genetics/*metabolism Cell culture DNA-Binding Proteins/genetics/metabolism 10032 Clinic for Oncology and Hematology HIV-1 biology.protein 570 Life sciences Carrier Proteins Anti-HIV Agents/*metabolism 030215 immunology |
| Zdroj: | Journal of Clinical Investigation, Vol. 119, No 10 (2009) pp. 3035-3047 The Journal of clinical investigation |
| ISSN: | 0021-9738 |
| Popis: | New World monkeys of the genus Aotus synthesize a fusion protein (AoT5Cyp) containing tripartite motif-containing 5 (TRIM5) and cyclophilin A (CypA) that potently blocks HIV-1 infection. We attempted to generate a human HIV-1 inhibitor modeled after AoT5Cyp, by fusing human CypA to human TRIM5 (hT5Cyp). Of 13 constructs, 3 showed substantial HIV-1-inhibitory activity when expressed in human cell lines. This activity required capsid binding by CypA and correlated with CypA linkage to the TRIM5a capsid-specificity determinant and the ability to form cytoplasmic bodies. CXCR4- and CCR5-tropic HIV-1 clones and primary isolates were inhibited from infecting multiple human macrophage and T cell lines and primary cells by hT5Cyp, as were HIV-2ROD, SIVAGMtan, FIVPET, and a circulating HIV-1 isolate previously reported to be AoT5Cyp resistant. The anti-HIV-1 activity of hT5Cyp was surprisingly more effective than that of the well-characterized rhesus TRIM5alpha, especially in T cells. hT5Cyp also blocked HIV-1 infection of primary CD4+ T cells and macrophages and conferred a survival advantage to these cells without disrupting their function. Extensive attempts to elicit HIV-1 resistance to hT5Cyp were unsuccessful. Finally, Rag2-/-gammac-/- mice were engrafted with human CD4+ T cells that had been transduced by optimized lentiviral vectors bearing hT5Cyp. Upon challenge with HIV-1, these mice showed decreased viremia and productive infection in lymphoid organs and preserved numbers of human CD4+ T cells. We conclude that hT5Cyp is an extraordinarily robust inhibitor of HIV-1 replication and a promising anti-HIV-1 gene therapy candidate. |
| Databáze: | OpenAIRE |
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