Abstract
Adoptive transfer of genetically-modified T cells is a promising approach for treatment of both human malignancies and viral infections. Due to its ability to efficiently infect lymphocytes, the chimeric adenovirus Ad5F35 is potentially useful as an immunotherapeutic for the genetic modification of T cells. In previous studies, it was found that the infection efficiency of Ad5F35 was significantly increased without enhanced expression of the viral receptor after T cell stimulation; however, little is known about the underlying mechanism. Nonetheless, cell physiology has long been thought to affect viral infection. Therefore, we aimed to uncover the physiologic changes responsible for the increased infection efficiency of Ad5F35 following T cell stimulation. Given the complexity of intracellular transport we analyzed viral binding, entry, and escape using a Jurkat T cell model and found that both cell membrane fluidity and endosomal escape of Ad5F35 were altered under different physiological states. This, in turn, resulted in differences in the amount of virus entering cells and reaching the cytoplasm. These results provide additional insight into the molecular mechanisms underlying Ad5F35 infection of T cells and consequently, will help further the clinical application of genetically-modified T cells for immunotherapy.
Highlights
We aimed to uncover the physiologic changes in T cells responsible for the increased Ad5F35 infection efficiency
We assessed the expression of CD80 and CD86 on T cells after stimulation and found there to be no difference from that seen on resting cells (Fig. 1c,d)
Gene transfer to T cells has mainly focused on viral vector systems[4,22]
Summary
We aimed to uncover the physiologic changes in T cells responsible for the increased Ad5F35 infection efficiency. Given the activated status of Jurkat cells, the serum starvation method was used to inversely induce changes in the physiological state of Jurkat cells, which successfully replicated the observed in vitro phenomenon of altered efficiency of viral infection without changes in the membrane expression of viral entry receptors. Entry, and escape of Ad5F35 and found that changes to the physiological state of T cells can significantly alter the processes of viral entry and escape. These results form the foundation for use of this viral vector for adoptive immunotherapy based on the genetic modification of T cells
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