Transmembrane protein aptamers that inhibit CCR5 expression and HIV co-receptor function.

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Transmembrane protein aptamers that inhibit CCR5 expression and HIV co-receptor function.

J Virol. 2012 Jul 18;

Authors: Scheideman EH, Marlatt SA, Xie Y, Hu Y, Sutton RE, Dimaio D

Abstract
We have exploited the ability of transmembrane domains to engage in highly-specific protein-protein interactions to construct a new class of small proteins that inhibit HIV infection. By screening a library encoding hundreds of thousands of artificial transmembrane proteins with randomized transmembrane domains ("traptamers"), we isolated six 44- or 45-amino acid proteins with completely different transmembrane sequences that inhibited cell-surface and total expression of the HIV co-receptor CCR5. The traptamers inhibited transduction of human T-cells by HIV reporter viruses pseudotyped with R5-tropic gp120 envelope proteins, but had minimal effects on reporter viruses with X4-tropic gp120. Optimization of two traptamers significantly increased their activity and resulted in greater than 95% inhibition of R5-tropic reporter virus transduction, without inhibiting expression of CD4, the primary HIV receptor, or CXCR4, another HIV co-receptor. In addition, traptamers inhibited transduction mediated by a mutant R5-tropic gp120 protein resistant to Maraviroc, a small molecule CCR5 inhibitor, and they dramatically inhibited replication of an R5-tropic laboratory strain of HIV in a multi-cycle infection assay. Genetic experiments suggested that the active traptamers specifically interacted with the transmembrane domains of CCR5 and that some of the traptamers interacted with different portions of CCR5. Thus, we have constructed multiple proteins not found in nature that interfere with CCR5 expression and inhibit HIV infection. These proteins may be valuable tools to probe the organization of the transmembrane domains of CCR5 and their relationship to its biological activities, and they may serve as starting points to develop new strategies to inhibit HIV infection.

PMID: 22811524 [PubMed - as supplied by publisher]

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