期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 119, 期 10, 页码 3035-3047出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI39354
关键词
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资金
- NIH [RO1A136199, RO1A159159]
- Swiss National Science Foundation [3100A0-113558, 3100A0-102218]
- Bill and Melinda Gates Foundation
- Melinda Gates Foundation
- Columbia University College of Physicians and Surgeons Medical Scientist
- Roche Research Foundation
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-2(ROD), SIV(AGM)tan, 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 TRIM5 alpha, 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(-/-)gamma c(-/-) 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.
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