Correlation of Interferon-Induced Expression of MxA mRNA in Peripheral Blood Mononuclear Cells with the Response of Patients with Chronic Active Hepatitis C to IFN-alpha Therapy

Abstract

MxA, a protein with selective activity against certain viruses, is an accepted specific indicator of type I interferon (IFN) activity. We have developed an internally controlled quantitative-competitive PCR to measure the amounts of MxA mRNA expressed in peripheral blood mononuclear cells (PBMC). This assay is more sensitive, quantitative, and easily applied to serial clinical samples than previously described methods. We have applied this assay retrospectively to 27 patients with chronic active hepatitis C given IFN-alpha2. Most such patients gain no sustained benefit but nevertheless suffer from the side effects, expense, and inconvenience of the treatment. Fourteen of the 27 had been classified on clinical grounds as responders and 13 as nonresponders at the end of a 6 month treatment period. We measured MxA mRNA in PBMC obtained before and after 8 weeks of IFN-alpha2 treatment. All the patients expressed some level of mRNA before treatment began, and after 8 weeks of treatment, the level rose in 19. This increase was significant (p < 0.001) only in patients classified as responders. This strongly suggests that hepatitis C virus (HCV) patients who express increased amounts of MxA mRNA in their PBMC during IFN-alpha treatment are most likely to obtain long-term benefit. If this finding is confirmed in future prospective studies, it will provide an extremely important predictive marker for managing IFN-alpha therapy in patients with HCV.

Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR

“…Clinical studies have also suggested that those who respond to interferon-a treatment express increased amounts of MxA mRNA during treatment. 6 Hijikata et al 23 describe a second SNP at position À123 from the transcription start site, which is in close linkage disequilibrium with the SNP at position À88, and was therefore ignored in our analysis.…”

“…5 Similarly, MxA mRNA levels have been reported to increase significantly after initiation of interferon therapy only in those who ultimately respond to treatment. 6 Upon binding to dsRNA, OAS-1 catalyses the formation of 2 0 -5 0 -linked oligoadenylate and activates RNAseL, which breaks down viral and cellular RNA. 7,8 PKR is also activated by dsRNA; this leads to the phosphorylation of its substrate, eIF2a, which inhibits the guanosine nucleotide exchange factor, eIF2b, and halts viral replication.…”

Rapid and simple detection of IFN‐neutralizing antibodies in chronic hepatitis C non‐responsive to IFN‐α

“…MxA expression in PBMCs has been reported to be a highly specific and reliable marker for type I IFN bioactivity during IFN treatment or viral infections [Jakschies et al, 1994;Roers et al, 1994;Chieux et al, 1998;Meier et al, 2000;Pachner et al, 2003]. Furthermore, MxA has been used as a predictive marker of sustained antiviral response in chronically HCV-infected patients undergoing IFN therapy [Antonelli et al, 1999;Fernandez et al, 1999].…”

Pharmacogenomic perspectives of chronic hepatitis C virus (HCV) infection

“…9 Other compelling evidence suggests that SR patients do have increased MX1 mRNA production and elevated MX1 protein level during treatment. 10 Thus, the pharmacogenetic and experimental findings are internally and externally consistent with a convincing causal relationship.…”