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

Neagu, Martha Raluca; Ziegler, Patrick; Pertel, Thomas; Strambio-De-Castillia, Caterina; Grutter, Christian; Martinetti, Gladys; Mazzucchelli, Luca; Grutter, Markus; Manz, Markus G.; Luban, Jeremy

doi:10.1172/JCI39354

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Title		Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components
Authors		Neagu, Martha Raluca Ziegler, Patrick Pertel, Thomas Strambio-De-Castillia, Caterina Grutter, Christian Martinetti, Gladys Mazzucchelli, Luca Grutter, Markus Manz, Markus G. Luban, Jeremy show all authors [1 - 10]
Published in		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 Transfer — Amino Acid Sequence — Animals — Anti-HIV Agents/metabolism — Aotidae — CD4-Positive T-Lymphocytes/cytology/immunology — Carrier Proteins/genetics/metabolism — Cell Line — Cyclophilin A/genetics/metabolism — DNA-Binding Proteins/genetics/metabolism — HIV-1/metabolism — Humans — Mice — Mice, Knockout — Models, Molecular — Molecular Sequence Data — Protein Conformation — Protein Engineering — Recombinant Fusion Proteins/genetics/*metabolism
Identifiers		DOI: 10.1172/JCI39354 PMID: 19741300
Full text		Article - Limited access to UNIGE
Structures		Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire
Research group		Réplication virale, pathogénèse et immunité (848)
Citation (ISO format)		NEAGU, Martha Raluca et al. Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. In: Journal of Clinical Investigation, 2009, vol. 119, n° 10, p. 3035-3047. doi: 10.1172/JCI39354 https://archive-ouverte.unige.ch/unige:19999