Mismatched Double-Stranded Rna (Ampligen) Reduces Concentration of Zidovudine (Azidothymidine) Required for in-Vitro Inhibition of Human Immunodeficiency Virus

Mitchell, W M; Montefiori, D. C.; Robinson, William E.; Strayer, David R.; Carter, WilliamA.

doi:10.1016/s0140-6736(87)92862-5

Cited by 46 publications

(7 citation statements)

References 11 publications

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“…Based on a priori considerations of charge-based associations and an awareness of reports that they inhibit HIV-1 entry in vitro , we suspected that the highly polyanionic polynucleotides poly(I·C) and CpG (ODN 1826) interact directly with cationic regions of the trimer ( 13 – 19 ). We found indications that this could, in fact, take place.…”

Section: Discussionmentioning

confidence: 99%

“…For example, there is evidence that complete Freund's adjuvant impairs the conformational integrity of monomeric gp120, probably because its oil-based components disrupt stabilizing interactions within the hydrophobic core of the protein ( 11 , 12 ). Polyanions, such as the RNA mimic poly(I·C), can inhibit HIV-1 infection in vitro , most likely via a charge-based interaction that compromises the natural functions of the virion-associated trimer ( 13 – 19 ). In principle, this type of association could occur with SOSIP trimer immunogens.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Adjuvants on HIV-1 Envelope Glycoprotein SOSIP Trimers In Vitro

Ozorowski

Cupo

Golabek

et al. 2018

J Virol

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Native-like, soluble, recombinant SOSIP trimers of various designs and based on several env genes of human immunodeficiency virus type 1 (HIV-1) are being tested as immunogens in different animal models. These experiments almost always involve coformulating the trimers with an adjuvant to boost the magnitude of the immune responses. One factor relevant to the choice of an adjuvant is that it should not physically damage the immunogen or impede its ability to present relevant epitopes. As examples, an adjuvant formulation that includes harsh detergents could disrupt the structural integrity of a trimer, and any charged compounds in the formulation could bind to countercharged regions of the trimer and physically occlude nearby epitopes. While a few adjuvants have been tested for their potential effects on SOSIP trimers in vitro, there has been no systematic study. Here, we have assessed how nine different adjuvants of various compositions affect SOSIP trimers of the BG505 and B41 genotypes. We used negative-stain electron microscopy, thermal denaturation, and gel electrophoresis to evaluate effects on trimer integrity and immunoassays to measure effects on the presentation of various epitopes. We conclude that most of the tested adjuvants are benign from these perspectives, but some raise grounds for concern. An acidified alum formulation is highly disruptive to trimer integrity, and a DNA-based polyanionic CpG oligodeoxynucleotide adjuvant binds to trimers and occludes the trimer apex epitope for the PGT145 neutralizing antibody. The methods described here should be generalizable to protein subunit vaccines targeting various pathogens.IMPORTANCE Adjuvant formulations increase the magnitude of immune responses to vaccine antigens. They are critically important for formulation of HIV-1 envelope glycoprotein (Env) vaccines intended to induce antibody production, as Env proteins are otherwise only very weakly immunogenic. The HIV-1 vaccine field now uses the well-defined structures of trimeric Env glycoproteins, like SOSIPs, to present multiple known epitopes for broad and potent neutralizing human antibodies in a native-like conformation. Successful adjuvant formulations must not disrupt how the trimers are folded, as that could adversely affect their performance as immunogens. We studied whether the various adjuvants most commonly used in animal experiments affect the integrity of two different SOSIP trimers in vitro. Most adjuvant classes are not problematic, but an aluminum sulfate formulation is highly damaging, as it exposes trimers to acidic pH and a nucleic acid-based adjuvant can bind to the trimer and block access to a key neutralizing epitope.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Adjuvants on HIV-1 Envelope Glycoprotein SOSIP Trimers In Vitro

Ozorowski

Cupo

Golabek

et al. 2018

J Virol

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“…Early studies demonstrated promise for poly(I:C) treatment in reducing the viral burden in HIV-infected individuals (10,52). Moreover, the antiviral effects of poly(I:C) were found to reduce the amounts of AZT required to limit HIV replication in vitro (42), and poly(I:C) was active against drug-resistant strains of HIV (20). With the advent of highly active antiretroviral therapy (HAART) in more recent years, additional antiviral strategies such as this may prove even more effective in helping to control infection while boosting immune function.…”

Section: Discussionmentioning

confidence: 99%

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

Trapp

Derby

Singer

et al. 2009

J Virol

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“…[9][10][11] The American Foundation for AIDS Research (AmFAR) currently lists the large number of various drugs being investigated for use in treating the AIDS-related complex (ARC) and AIDS.12 This multitude of potential single-agent therapies is compounded by possible synergism in combination therapies. Alternatively, combined therapy has the potential for antagonism as demonstrated in vitro with azidothymidine and ribavirin.13 For these reasons we decided to characterize more completely the potential of mismatched dsRNA in the treatment of ARC and AIDS by performing in vitro multiple drug analyses using mismatched dsRNA as a core drug in combination with other agents that together encompassed at least five different modes of attack on this virus.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Evaluation of Mismatched Double-Stranded RNA (Ampligen) for Combination Therapy in the Treatment of Acquired Immunodeficiency Syndrome

Montefiori

Robinson²,

Mitchell³

1989

AIDS Research and Human Retroviruses

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Multiple drug effect analyses with mismatched double-stranded RNA (mismatched dsRNA or Ampligen) as a core drug were performed to identify other agents and mechanisms through which mismatched dsRNA may potentiate effective therapeutic intervention in human immunodeficiency virus (HIV) infection. Antiviral activities were defined by a microtiter infection assay utilizing MT-2 cells as targets and HTLV-III-B produced in H9 cells as a virus source. The scope of agents tested included rIFN-alpha A, rIFN-beta Ser 17, and rIFN-gamma as cytokines; azidothymidine and phosphonoformate (Foscarnet) as inhibitors of reverse transcription; ribavirin as a putative inhibitor of proper HIV mRNA capping; amphotericin B as a lipophile; and castanospermine as a glycoprotein processing (glucosidase I) inhibitor. Separately, each drug demonstrated dose-dependent anti-HIV activity and, when used in combination with mismatched dsRNA, demonstrated synergism. Although mismatched dsRNA was synergistic with all three IFNs for anti-HIV activity in microtiter infection assays, it did not potentiate the transient inhibition of virus production observed for IFN in cultures of H9/HTLV-III-B cells. The results of these studies suggest that the pleiotropic activities of dsRNAs differ from those of IFN and may provide synergism in combination therapy with a wide range of antiviral drugs for the treatment of the acquired immunodeficiency syndrome (AIDS).

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Mismatched Double-Stranded Rna (Ampligen) Reduces Concentration of Zidovudine (Azidothymidine) Required for in-Vitro Inhibition of Human Immunodeficiency Virus

Cited by 46 publications

References 11 publications

Effects of Adjuvants on HIV-1 Envelope Glycoprotein SOSIP Trimers In Vitro

Effects of Adjuvants on HIV-1 Envelope Glycoprotein SOSIP Trimers In Vitro

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

In Vitro Evaluation of Mismatched Double-Stranded RNA (Ampligen) for Combination Therapy in the Treatment of Acquired Immunodeficiency Syndrome

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