63. Re-Directed Herpes Simplex Virus Infection by a Soluble, Bi-Specific Adapter Protein for gD in Combination with Nectin-1 Blocking Agents

Abstract

One of the landmarks of advanced liver cirrhosis is the decrease of serum IGF-I levels probably due to its diminished synthesis from liver parenchyma. Patients with liver cirrhosis have a number of systemic derangements related to the reduced levels of circulating IGF-I. The administration of recombinant IGF-I in physiological doses reverts these symptoms and partially, the cirrhosis state. Recombinant viruses expressing a therapeutic protein are being used as an alternative for recombinant protein administration. We decided to study the efficiency of an IGF-I expressing recombinant vector based on Simian Virus 40 virus (SV40) to prevent liver cirrhosis in a rat model. Recombinant SV40 vectors have several advantages for this purpose. They efficiently infect hepatocytes, they have a long-term expression and they are non-immunogenic. We have produced recombinant viruses expressing firefly luciferase (rSVLuc) and rat IGFI-I (rSVIGF-I). Expression, secretion and activity of IGF-I by rSVIGF has been demonstrated in vitro by RIA and AKT activation in 3T3 cells. rSVLuc mouse liver infection has been visualised with a CCD camera for more than six moths. Luciferase liver expression in rSVLuc infected mice increased during liver regeneration, after CCl4 administration and in response to IGF-I. Healthy male Wistar rats were mock infected or intraportaly infected with rSVLuc or rSVIGF-I. Cirrhosis was induced by CCl4 inhalations during 36 weeks. rSVIGF-I infected rats had normal levels of transaminases, bilirubin and IGF-I binding proteins (IGFBPs) and a significant increase in IGFBP3, regulated by IGF-I. Control groups, saline and rSVLUC treated rats, had altered serum parameters, a significant decrease in testis weight and an increase in liver fibrosis formation. Quantitative RT-PCR from liver samples showed an increase in collagen, Timp1a and MIP1a expression and a decrease in IGF-I, HGF and IGFBP3 expression in control groups vs rSVIGF-I infected rats. These results indicate that the rSVIGF-I vector could be an efficient alternative for prevention and treatment of liver cirrhosis development.