The homeostatic activities of empty SV40 capsids in their interactions with the host

Empty SV40 capsids (nanocapsids-NCs) induce signaling networks upon cell recognition and entry. Our gene therapy experiments directed at toxic Acute Kidney Injury (AKI), inflicted on mice by mercury, unexpectedly demonstrated that the control empty capsids provided higher survival efficacy than the vector carrying Hsp70. AKI leads to apoptosis and necrosis of kidney epithelial cells; the NCs induced Akt-1 survival pathway in addition to Hsp70. Although Akt-1 is an oncogene, proliferation of kidney cells was not seen. Experiments in cultured cells demonstrated that the NCs partially reverse the effect of both growth stimulators and inhibitors. The mechanism relies on calcium signaling, a central regulator of cell fate, activated minutes following NC addition to the cells. Our recent study in a severe rat sepsis model, induced by cecal ligation and double puncture (2CLP), demonstrated that while all the vehicle-treated rats died within 4 days, 75% of the septic rats pretreated by NCs survived and fully recovered. RNAseq studies on lung-derived RNA demonstrated that unlike AKI, here the NCs did not induce survival pathways. Instead they affected thousands of other genes and many cellular functions, eliminating deleterious pathways and inducing beneficial ones: immune response regulation, resolution of inflammation, regeneration and cell and system homeostasis. In contrast, only four genes were affected following nanoparticle administration to healthy rats. We propose that SV40 NCs respond specifically to perturbation in cellular and systemic homeostasis. It appears that during virus-host coevolution SV40 gained the properties that enable it to keep the organism healthy, ensuring its maximal propagation.