Clinical, Immunological, and Virological Effects of Ampligen, a Mismatched Double-Stranded Rna, in Patients With Aids or Aids-Related Complex

Carter, WilliamA.; Brodsky, Isadore; Pellegrino, MichaelG.; Henriques, H. F.; Parenti, D. M.; Schulof, Richard S.; Robinson, William E.; Volsky, D. J.; Paxton, Helene; Karikó, Katalin; Suhadolnik, RobertJ.; Strayer, David R.; Lewin, Mark B.; Einck, Leo; Simon, GaryL.; Scheib, RochelleG.; Montefiori, D. C.; Mitchell, W M; Paul, Deborah A.; Meyer, WilliamA.; Reichenbach, Nancy L.; Gillespie, D. A. F.

doi:10.1016/s0140-6736(87)90543-5

Cited by 112 publications

(30 citation statements)

References 15 publications

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“…Poly(I:C 12 U) is an experimental drug that has been shown to have varying degrees of antiviral activity against HIV (28,29), hepatitis B virus (30), several flaviviruses (31,32), and coxsackie B3 virus (33). We have also demonstrated remarkable efficacy using poly(I: C 12 U), as well as poly(I:C), in the mouse PTV infection model (5,10).…”

Section: Discussionmentioning

confidence: 85%

TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules

Gowen

Wong

Jung

et al. 2007

The Journal of Immunology

103

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In the wake of RNA virus infections, dsRNA intermediates are often generated. These viral pathogen-associated molecular patterns can be sensed by a growing number of host cell cytosolic proteins and TLR3, which contribute to the induction of antiviral defenses. Recent evidence indicates that melanoma differentiation-associated gene-5 is the prominent host component mediating IFN production after exposure to the dsRNA analog, poly(I:C). We have previously reported that Punta Toro virus (PTV) infection in mice is exquisitely sensitive to treatment with poly(I:C12U), a dsRNA analog that has a superior safety profile while maintaining the beneficial activity of the parental poly(I:C) in the induction of innate immune responses. The precise host factor(s) mediating protective immunity following its administration remain to be elucidated. To assess the role of TLR3 in this process, mice lacking the receptor were used to investigate the induction of protective immunity, type I IFNs, and IL-6 following treatment. Unlike wild-type mice, those lacking TLR3 were not protected against PTV infection following poly(I:C12U) therapy and failed to produce IFN-α, IFN-β, and IL-6. In contrast, poly(I:C) treatment significantly protected TLR3−/− mice from lethal challenge despite some deficiencies in cytokine induction. There was no indication that the lack of protection was due to the fact that TLR3-deficient mice had a reduced capacity to fight infection because they were not found to be more susceptible to PTV. We conclude that TLR3 is essential to the induction of antiviral activity elicited by poly(I:C12U), which does not appear to be recognized by the cytosolic sensor of poly(I:C), melanoma differentiation-associated gene-5.

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Section: Discussionmentioning

confidence: 85%

TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules

Gowen

Wong

Jung

et al. 2007

The Journal of Immunology

103

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“…Poly(I).poly(C~2U) seems also to have the ability to restore immunological function, and to control both HIV replication (Carter et al, 1987;Laurence et al, 1987;Montefiori et al, 1989 a) and herpes simplex virus type 2 infection (Aurelian et al, 1987). Furthermore, poly (I).poly(C12U) is a more potent anti-HIV agent than IFN-~, IFN-fl or IFN-% or all three IFNs combined (Montefiori & Mitchell, 1987), and acts synergistically with IFN or azidothymidine in inhibiting HIV infection (Montefiori et al, 1989b;.…”

Section: Discussionmentioning

confidence: 99%

The effects of poly(I).poly(C12U) and interferon on the multiplication of a mammalian type C retrovirus in human cells

Chelbi-Alix

Belforte

Saal

et al. 1992

Journal of General Virology

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“…D. Strayer (personal communication) has proposed that the chance of cancer response is linked to direct antitumor actions of dsRNA, while the duration of responses is more related to immune enhancement. pI:C,U was reported to have beneficial effects in 10 HIV disease patients [119]. T4 cell numbers stabilized, delayed cutaneous hypersensitivity returned, and HlV load slowly decreased.…”

Section: Clinical Applicationsmentioning

confidence: 97%

“…The effects in HIV disease may have to do with an intrinsic defect in the 2,5A synthetase pathway in PBMC. It is reported that PBMC of ARC and AIDS patients have elevated levels of latent 2,5A synthetase [119,120,121] and low to undetectable levels of activated RNase L [118,119,1211. After administering pI:C,U for several weeks, these values normalized [119,121].…”

Section: Clinical Applicationsmentioning

confidence: 99%

“…It is reported that PBMC of ARC and AIDS patients have elevated levels of latent 2,5A synthetase [119,120,121] and low to undetectable levels of activated RNase L [118,119,1211. After administering pI:C,U for several weeks, these values normalized [119,121]. It is unlikely that the observed 2,5A synthetaseIRNase L defect is the disturbance in the pathway resulting from HIV infection which has been observed in vitro [69], because so few PBMC are infected in vivo.…”

Section: Clinical Applicationsmentioning

confidence: 99%

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Cellular response to double‐stranded RNA

Haines¹,

Strauss²,

Gillespie³

1991

J of Cellular Biochemistry

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The study of double-stranded RNA (dsRNA) encompasses a variety of fields. Basic research in this area has contributed to a greater mechanistic understanding of gene induction, tumor cell growth arrest, the establishment of antiviral states, and immunomodulation. Because of the possible clinical value of these molecules, physicians are now exploring the use of synthetic dsRNA to treat patients with cancer, HIV-1 disease, and immune dysfunction. Continued studies of the mechanisms of action of dsRNA are likely to suggest an even wider scope of clinical applications.

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Clinical, Immunological, and Virological Effects of Ampligen, a Mismatched Double-Stranded Rna, in Patients With Aids or Aids-Related Complex

Cited by 112 publications

References 15 publications

TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules

TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules

The effects of poly(I).poly(C12U) and interferon on the multiplication of a mammalian type C retrovirus in human cells

Cellular response to double‐stranded RNA

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