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Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components

Ziegler, Patrick
Strambio-De-Castillia, Caterina
Grutter, Christian
Martinetti, Gladys
Mazzucchelli, Luca
Grutter, Markus
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Published in The Journal of clinical investigation. 2009, vol. 119, no. 10, p. 3035-3047
Abstract 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.
Keywords Adoptive TransferAmino Acid SequenceAnimalsAnti-HIV Agents/*metabolismAotidaeCD4-Positive T-Lymphocytes/cytology/immunologyCarrier Proteins/genetics/*metabolismCell LineCyclophilin A/genetics/*metabolismDNA-Binding Proteins/genetics/metabolismHIV-1/*metabolismHumansMiceMice, KnockoutModels, MolecularMolecular Sequence DataProtein ConformationProtein EngineeringRecombinant Fusion Proteins/genetics/*metabolism
PMID: 19741300
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Research group Réplication virale, pathogénèse et immunité (848)
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NEAGU, Martha Raluca et al. Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. In: The Journal of clinical investigation, 2009, vol. 119, n° 10, p. 3035-3047. doi: 10.1172/JCI39354 https://archive-ouverte.unige.ch/unige:19999

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Deposited on : 2012-04-23

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