Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-21156
Neagu, M R; Ziegler, P; Pertel, T; Strambio-De-Castillia, C; Grütter, C; Martinetti, G; Mazzucchelli, L; Grütter, M; Manz, M G; Luban, J (2009). Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. Journal of Clinical Investigation, 119(10):3035-3047.
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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Biochemistry|
07 Faculty of Science > Institute of Biochemistry
04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||12 Oct 2009 14:26|
|Last Modified:||23 Nov 2012 15:32|
|Publisher:||American Society for Clinical Investigation|
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