Limited Efficacy of Antiherpetic Drugs
Study of the Nature of Limited Efficacy of Drugs Used for the Therapy of Diseases Caused by Herpes Simplex Virus Type 1
Tech Area / Field
- MED-DID/Diagnostics & Devices/Medicine
- MED-DRG/Drug Discovery/Medicine
8 Project completed
Senior Project Manager
Gremyakova T A
Gamalei Institute of Epidemiology and Microbiology, Russia, Moscow
- University of Ottawa, Canada, ON, Ottawa
Project summaryThe large part of human population is infected with herpes virus simplex type 1 (HSV-1) (Klein R.J., 1982; Nahmias A, Josey K., 1987). Use of medical preparations (interferon, interferon inducers, and antiviral drugs) arrests acute phase of the disease and leads to the development and maintenance of HSV-1 latency (Barinski I.F. et al., 1986). In addition to latency of HSV-1 in neural ganglia (Halford W.R. et al., 1996; Millhouse S., Wigdahl B., 2000) this virus has also been found in the blood vessels endothelium in biopsy material of various organs (; Herszum M., et al., 1998; Holbach L.M. et al., 1998). There is solid evidence suggesting a link between HSV-1 infection and the development of atherosclerosis of blood vessels (Nicholson A.C., Hajjar D.P., 1998). All these data support a hypothesis about the involvement of cell populations of blood vessel walls and, particularly, endothelium lining inner part of vessels in the pathogenesis of herpetic disease caused by HSV-1.
Blood vessel wall is a complex biological system endowed with multiple functions in organism (Fishman A.P., 1982; Belke M.A., 1989; Mantjvani A. Et al., 1992; Cines D.B. et al., 1998). Vascular endothelium is a semi-permeable barrier between blood and organs, participates in the functioning of the immune system, regulate vessel tone, provide for blood flow through maintaining antithrombotic and fibrinolytic phenotype via expressed and synthesized factors, which are the markers of the functional activity of endothelium. Vascular endothelium is involved in the pathogenesis of various diseases, including infections diseases, which result in endothelium dysfunction, which in its turn, provides the bases for the development of pathological processes, i.e. thrombosis, atherosclerosis, tumor dissemination, transplant rejection, angiogenesis, and others (Peters K. et al., 2003, Prasad A. et al., 2000, Chi D. et al., 2000).
Functional activity of endothelium can be characterized in cultured human blood vessel endothelium using the following markers: (1) markers of inflammatory activity: (a) cell adhesion molecules (CAM) (McEver R.P. et al., 1995; Walcheck B. et al., 1996); (b) cytokines, chemokines, growth factors (Bradley J.R., Pober J.S. 1996); (2) procoagulant activity marker: von Willebrand factor (vWF) (Wagner D.D., Bonfani R., 1991); (3) fibrinolytic activity marker: tissue plasminogen activator (tPA) (McCrae K.R. et al., 1994); (4) markers of vessel tone regulation: nitric oxide (NO) and endothelin-1 (ET-1) (Loscalzo J., Welch G., 1995, Levin E.R, 1996); (6) agiogenesis marker: matrix metalloproteinase 1 (ММР-1) (Breier G., Risau W., 1996); (7). apoptosis markers.
These factors, which are markers of the functional activity of endothelium, have pleiotropic functions, since intracellular transduction mechanisms for different factors are common (Cines D.B. et al., 1998, McGill S.N. et al., 1998).
A model to study the interaction of HSV-1 with the primary culture of human blood vessel endothelium (EC) has been developed and is characterized by virus reproduction and changes in the functional state of cells, that is, their phenotype changed for proinflammatory and prothrombogenic, decreased prostacyclin synthesis and enhanced secretion of von Willebrand factor (Vercelotti G.M., 1998). Interferon (IFN) and IFN inducers (IFNi) used for the therapy of patients with HSV-1 infection enter the bloodstream and contact with blood cells and endothelium directly or via the production of immune mediators induced by them. The effects of IFN and IFNi may lead both to the development of antiviral status in EC and to the establishment of viral latency which can became the basis for chronic inflammation in the vascular wall and chronic dysfunction of endothelium. There is scarce information about the effect of IFN and IFNi on the functional state of intact or infected vascular endothelium. Interrelations between the expression of the markers of the functional state of intact and infected vascular endothelium and the effects of IFN and IFNi have not yet been studied through the assessment of antiviral status and changes in the expression of EC markers.
The goal of the study is to investigate interrelations between the efficacy of influence of interferon preparations on cultured human endothelial cells infected with HSV-1 and the expression of markers of the functional state of endothelium.
- To study the dependence between the development of anti-HSV-1 status and synthesis of specific markers by cultured human endothelial cells exposed to interferon-α.
- To study the dependence between the development of anti-HSV-1 status and synthesis of specific markers by cultured human endothelial cells exposed to interferon-β.
- To study the dependence between the development of anti-HSV-1 status and synthesis of specific markers by cultured human endothelial cells exposed to double-stranded RNA, interferon inducer.