Synergistic Interaction of Interferon-  and Interferon-  in Coxsackievirus B3-Infected Carrier Cultures of Human Myocardial Fibroblasts

Abstract

The antiviral effects of human interferon-beta (IFN-beta) and human recombinant interferon-gamma (rIFN-gamma) were studied in persistently coxsackievirus B3-infected carrier cultures of human myocardial fibroblasts over a period of 21 days. Synergism was observed with concentrations as low as 30 IU of IFN-beta plus 10 IU of rIFN-gamma/mL, reducing mean viral titers from 6.0 x 10(7) to 1.3 x 10(4) pfu/mL and number of infected cells from 14.4% to 0.1% as determined by quantitative in situ hybridization. Higher concentrations of IFNs (both > or = 30 IU/mL) were associated with transient antagonism followed by antiviral synergism. With 100 IU of IFN-beta plus 30 IU of rIFN-gamma/mL, elimination of infectious virus was consistently achieved and sustained for 6 weeks after cessation of IFN application, whereas at least threefold higher concentrations were required with single drugs. In summary, our data support a concept of low-dose IFN combination schedules that might become useful in the treatment of enteroviral heart disease.

Persistent Infection of Human Microvascular Endothelial Cells by Coxsackie B Viruses Induces Increased Expression of Adhesion Molecules

“…Stability of the cell membrane could also be another important factor in the ability of infected cells to survive infection, without lysis. In previous studies, the distinct susceptibility of different cell types to long-term infection has been related to the production of IFNs (15,35).…”

“…However, it cannot be excluded that TNF-␣ produced by infected cells may synergize with the other cytokines in enhancing expression of adhesion proteins, extravasation of leukocytes, and differentiation and proliferation of lymphocytes (25,32,41). Cytokineblocking experiments only partially reduced expression of adhesion molecules, indicating that besides IL-6 and IL-8, other molecules, such as IFNs (15,35) or IL-1 (42), may contribute to the up-regulation of ICAM-1 and VCAM-1 (41).…”

Islet Endothelium: Role in Type 1 Diabetes and in Coxsackievirus Infections

“…Endothelial cells themselves may serve as antigen-presenting cells Savinov et al, 2003). The infection was also accompanied by increased production of IFN-, that has a role in initiation and maintenance of chronic CVB infection, as shown for other infected cell lines including islet  cells, and in line with the extensive studies documenting abnormal localization of IFN- in the pancreas of type 1 diabetic patients , Huber et al, 1990, Conaldi et al, 1997Heim et al, 1992). As stated above, IFN- may be responsible for a viral expansion of non-specific T cell responses, including autoreactive T cells.…”

“…Stability of the cell membrane could also be another important factor in the ability of infected cells to survive infection, without lysis. In previous studies, the distinct susceptibility of different cell types to long-term infection has been related to the production of interferons (Conaldi et al, 1997;Heim et al, 1992). It has also been suggested that the persistent infection of cultured HUVEC may be due to down-regulation of viral receptors in infected cells.…”

Profiling Subcellular Protein Phosphatase Responses to Coxsackievirus B3 Infection of Cardiomyocytes

“…Type II interferon (IFN␥) signaling is initiated by the paracrine action of natural killer cells, which become activated upon CVB3 infection (44). Cotreatment of cells with IFN␤ and IFN␥ synergistically inhibits CVB3 replication (104), and IFN␤ treatment alone has shown some success in clearing persistent CVB3 infections (98). Phosphatases are rare among interferon-stimulated genes (105), but some viruses directly perturb interferon action by upregulating phosphatase activity (106).…”