Recombinant Human Interferon Alfa-a Suppresses HTLV-Iii Replication in Vitro

Dd, Ho; Rota, Teresa R.; Kaplan, Jerome I.; Hartshorn, Kevan L.; Andrews, CharlaA.; Schooley, R. T.; Hirsch, M. S.

doi:10.1016/s0140-6736(85)92144-0

Cited by 282 publications

(87 citation statements)

References 18 publications

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“…Agents such as RT inhibitors [22] which block retroviral replication, act at early stages of the viral infection process, while other agents, such as a-interferon, have been reported to suppress retroviral expression in chronically infected cells [23]. Tyrphostins appear to act as antiviral drugs at both levels and, under certain conditions, are capable of both blocking the initial stage of retroviral infection and reducing viral production in chronically infected cells thus, presenting potential advantages over drugs that function only on one level.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Moloney murine leukemia virus replication by tyrphostins, tyrosine kinase inhibitors

1994

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We have previously shown that topoisomerase I (topo I) antagonist inhibited retrovirus replication. Since tyrphostins, synthetic compounds and protein tyrosine kinases (PTKs) blockers, inhibited topo I activity (manuscript in preparation) we examined their ability to inhibit Moloney murine leukemia virus (MO-MuLV) replication. We found that non-cytotoxic doses of tyrphostin derivatives (AG-555, AG-18) blocked or substantially reduced MO-MuLV replication in acute or chronically infected NIH13T3 cells. Our experiments suggest that the antiviral effect of these tyrphostin derivatives was not the result of antiproliferative activity. However, the tyrphostin derivatives used in our present investigation differ in their ability to inhibit MO-MuLV replication. Furthermore, as expected from stereospecific competitive inhibitors, the antiviral effect is not a general characteristic of all tyrphostin derivatives, since AG-213 does not affect MO-MuLV replication. Our results indicate that these tyrphostin derivatives may represent a novel class of antiretroviral drugs.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Moloney murine leukemia virus replication by tyrphostins, tyrosine kinase inhibitors

1994

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“…HIV's effect on KS development and progression is indirect; it may contribute to the severity of the tumor by reducing the immune response to HHV-8, by stimulating the production of inflammatory cytokines, and by the release of its transactivator protein Tat, which acts synergistically with other angiogenic cytokines to stimulate spindle cell proliferation, adhesion and migration in vitro [49]. Although multiple studies attest to the inhibitory effect of IFNα on HIV replication and its synergistic inhibitory activity in combination with other antiretroviral agents in vitro [12,[50][51][52], it is not known to what extent (if any) inhibition of HIV contributes to IFN-induced KS regression.…”

Section: Antiviral Activitiesmentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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Interferon alfa (IFNA) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNα in KS treatment, little is currently known about the mechanism(s) by which IFNA causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNA activities. To a large extent other agents have supplanted IFNA as treatments for KS, but there may still remain a therapeutic role for IFNA, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling. KeywordsInterferon; Kaposi's sarcoma In 1995, when I was honored as a recipient of the ISICR Milstein Award, the AIDS epidemic had recently begun its 15 th year and the human immunodeficiency virus (HIV-1) had been isolated some 12 years previously [1]. However, the virus associated with Kaposi's sarcoma (KS), the most common AIDS-associated malignancy, had been described less than a year earlier [2], its significance was still in some question and its role in KS development had not been characterized, and the active combination drug regimens with which we now treat HIV infection had not yet become widely available. Recombinant interferon alfa preparations (IFNα2a and IFNα2b), which had received approval from the U.S. Food and Drug Administration (FDA) for treatment of AIDS-associated KS in 1988, were still the only approved drugs for systemic treatment of KS (the chemotherapeutic agent, liposomal doxorubicin, would receive FDA approval later in 1995, as did liposomal daunorubicin in 1996 and paclitaxel in 1997). Now, more than a quarter century after the first published reports describing AIDS and its association with KS [3-6] and our first modestly successful attempts to treat KS with IFNα [7], this agent is used infrequently to treat KS, although it still finds use in HIV-infected individuals co-infected with hepatitis C. In this brief review, I will summarize some of the history of IFNα in the treatment of AIDS-associated KS, concentrating on examples of clinical trials in which I have personally been involved, and consider whether there remains a potentially valuable role for this agent in KS treatment.

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“…The time period until onset of HIV-1 production can be extended in vitro by 2-5A analogues (MOiler et al, 1988;Montefiori et aI., 1989;Suhadolnik et al, 1989) interferon (Ho et al, 1985) or mismatched dsRNA . Transfection experiments using the 2-5A synthetase gene under the control of HIV-1 LTR revealed that the transfected cells become resistant against HIV-1 infection due '(0 the Tat-TAR-mediated expression of the synthetase after HIV-1 infection (Schroder et aI., 1990a).…”

Section: Resultsmentioning

confidence: 99%

Synergistic Anti-Human Immunodeficiency Viral (HIV-1) Effect of the Immunomodulator Ampligen (Mismatched Double-Stranded RNA) with Inhibitors of Reverse Transcriptase and HIV-1 Regulatory Proteins

Ushijima

Tsiapalis

Daum

et al. 1993

Antivir Chem Chemother

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The potent antiviral effect of double stranded RNA, such as the mismatched poly(l)·poly(C12U) [Ampligen], 2′,3′-dideoxy-3′-fluorothymidine (FddThd) and antisense oligodeoxynucleotides (ODN) has been established in in vitro systems using cells infected with the human immunodeficiency virus type 1 (HIV-1). We report here that the immunomodulator poly(l)·poly(C12U) interacts synergistically with (1) the reverse transcriptase inhibitor FddThd (FIC value: 0.43), (2) the modified (5′- and 3′-end capped thioates) antisense ODN-4 directed against the splice acceptor site of the HIV-1/ tat gene (FIC value: 0.66) and (3) also with pyronin Y, a compound which prevents binding of HIV-1 Rev protein to the HIV-1 RRE element. These data suggest that combinations of poly(l)·poly(C12U), a stimulator of the natural antiviral protection system of the cells, with compounds targeting HIV1-specific processes should be considered as candidate treatments of AIDS patients.

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Recombinant Human Interferon Alfa-a Suppresses HTLV-Iii Replication in Vitro

Cited by 282 publications

References 18 publications

Inhibition of Moloney murine leukemia virus replication by tyrphostins, tyrosine kinase inhibitors

Inhibition of Moloney murine leukemia virus replication by tyrphostins, tyrosine kinase inhibitors

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Synergistic Anti-Human Immunodeficiency Viral (HIV-1) Effect of the Immunomodulator Ampligen (Mismatched Double-Stranded RNA) with Inhibitors of Reverse Transcriptase and HIV-1 Regulatory Proteins

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