UP-REGULATION OF THE 2-5A SYNTHETASE RNASE L ANTIVIRAL PATHWAY ASSOCIATED WITH CHRONIC FATIGUE SYNDROME/

Levels of 2',5'-oligoadenylate (2-5A) synthetase, bioactive 2-5A, and RNase L were measured in extracts of peripheral blood mononuclear cell s (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) befo re and during therapy with the biological response modifier poly(I) po ly(C,,U) and were compared with levels in healthy controls. Patients d iffered significantly from controls in having a lower mean basal level of latent 2-5A synthetase (P < .0001), a higher pretreatment level of bioactive 2-5A (P = .002), and a higher level of pretherapy RNase L a ctivity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the correspondin g control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6). Ther apy with poly(I) poly(C12U) resulted in a significant decrease in HHV- 6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNas e L pathway in temporal association with clinical and neuropsychologic al improvement. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent vi ral infection in the pathogenesis of CFS. The response to therapy sugg ests direct or indirect antiviral activity of poly(I) poly(C12U) in th is situation.