Elevated Levels of Interferon-Induced 2'-5' Oligoadenylate Synthetase in Generalized Persistent Lymphadenopathy and the Acquired Immunodeficiency Syndrome

Abstract

The levels of the 2'-5' oligoadenylate enzyme synthetase in extracts of peripheral blood mononuclear cells from individuals with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) were measured and compared with synthetase levels in peripheral blood mononuclear cells (PBMs) from healthy heterosexual and homosexual controls. The mean basal synthetase level in heterosexual and homosexual controls was 14 +/- 13 and 12 +/- 9 pmol per hr/10(5) PBMs, respectively. Thirteen individuals with AIDS had a mean basal level of 129 +/- 75 pmol. Serial levels were persistently elevated in six of these individuals over a one- to 10-month period. Twelve of the 13 individuals had antibodies to human T cell lymphotrophic virus-III/lymphadenopathy-associated virus (HTLV-III/LAV). Thirty-three individuals with ARC had a mean basal synthetase level of 68 +/- 84 pmol. Thirty-two of the 33 had antibodies to HTLV-III/LAV. Eleven (33%) have had consistently normal synthetase levels (less than 2 SD above the mean for the homosexual controls, i.e., 30 pmol) over a three- to nine-month follow-up period. Fourteen (42%) had persistently elevated levels over the same period; four (29%) of these developed AIDS during the follow-up period. Eight have had fluctuating levels but have remained clinically well. These studies suggest that persistently elevated synthetase levels in individuals with ARC and antibodies to HTLV-III/LAV indicate progressive virus-induced disease activity. Elevated synthetase levels may be an important prognostic indicator of increased risk of progression to AIDS.

Downregulation of interferon alpha but not gamma receptor expression in vivo in the acquired immunodeficiency syndrome.

“…After overnight incubation without IFNa, the respective 2-5A synthetase levels decreased to 8.0±4.5, 27±38 and 45±25 pmol/h per 105 PBM (Table I). All the AIDS patients had persistent, significantly elevated levels of 2-5A synthetase (P < 0.001), consistent with earlier reports (18,36). However, in ARC patients, the enzymatic activities were more variable; they ranged from normal to a > 10-fold increase in basal activity in one case (patient 15, Table I).…”

“…Subsequent to washings, the cell pellets were frozen at -70°C until the time ofassay. 2-SA synthetase activities ofthe cellular extracts were determined using poly r(I):r(C) coated agarose beads (18,19 …”

“…The acidlabile IFN was also detected in two hemophiliac patients before the onset of AIDS (17). We have previously reported elevated levels of an IFN-induced intracellular enzyme, 2'-5' oligoadenylate (2-5A) synthetase,' activity in AIDS and AIDS-related complex (ARC) patients (18). Although the physiological and immunological significance ofthese elevated levels of IFN and 2-5A synthetase activity in the pathogenesis of AIDS is not known, there appears to be an association between persistent elevation of 2-5A synthetase activity in ARC patients and increased risk of developing AIDS (19).…”

Phosphorylation of HIV Tat by PKR increases interaction with TAR RNA and enhances transcription

“…However, while IFN is able to inhibit HIV-1 infection in vitro [4], it has not been effective in the treatment of HIV-1 infections in vivo . Furthermore, the presence of increasing levels of IFN in the serum of AIDS patients while viral replication continues and the disease progresses [5-7] indicates that HIV-1 must employ a mechanism to evade the antiviral effects of IFN.…”

Regulation of Tumor Necrosis Factor Receptor Expression by Acid-Labile Interferon-α from AIDS Sera

“…'2 We have previously reported that persistent elevation of an IFN-induced enzyme activity, 2-5A synthetase, in patients with HIV infection is indicative of disease progression from AIDS-related complex to AIDS. 3,4 We have also demonstrated down regulation of IFNa but not 7 receptor expression on peripheral blood monocytes (PBM) isolated from AIDS patients by the acid-labile IFNa. 5 Although the immunological significance of this IFN subtype in the pathogenesis of AIDS remains to be determined, IFNs have been shown to enhance the actions of TNF in cytotoxic, tumoricidal, antiviral, and antiproliferative activities.6"9…”