Upregulation 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 cells (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) before and during therapy with the biological response modifier poly(I).poly(C12U) and were compared with levels in healthy controls. Patients differed 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 activity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the corresponding control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6). Therapy with poly(I).poly(C12U) resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS. The response to therapy suggests direct or indirect antiviral activity of poly(I).poly(C12U) in this situation.
Suhadolnik
R J
RJ
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
Reichenbach
N L
NL
Hitzges
P
P
Sobol
R W
RW
Peterson
D L
DL
Henry
B
B
Ablashi
D V
DV
Müller
W E
WE
Schröder
H C
HC
Carter
W A
WA
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000378:metabolism; D000998:Antiviral Agents / Q000627:therapeutic use; D004722:Endoribonucleases / Q000378:metabolism*; D015673:Fatigue Syndrome, Chronic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009843:Oligoribonucleotides / Q000378:metabolism; D011070:Poly I-C / Q000627:therapeutic use; D011072:Poly U / Q000627:therapeutic use; D012330:RNA, Double-Stranded / Q000627:therapeutic use; D015854:Up-Regulation; D014777:Virus Diseases / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D009843:Oligoribonucleotides; D012330:RNA, Double-Stranded; D011072:Poly U; C023505:2',5'-oligoadenylate; C047490:poly(I).poly(c12,U); D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D011070:Poly I-C