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Phosphorothioate oligonucleotides inhibit the replication of lentiviruses and type D retroviruses, but not that of type C retroviruses

Identifieur interne : 004412 ( Main/Exploration ); précédent : 004411; suivant : 004413

Phosphorothioate oligonucleotides inhibit the replication of lentiviruses and type D retroviruses, but not that of type C retroviruses

Auteurs : D. Archambault [Canada] ; C. A. Stein [États-Unis] ; J. S. Cohen [États-Unis]

Source :

RBID : ISTEX:DADABF9DCBE12AC0B779B22B9C0B1E0170E9770C

Descripteurs français

English descriptors

Abstract

Summary: Phosphorothioate analogs of oligodeoxynucleotides at a concentration of 2µM protected Himalayan tahr cells from infection by caprine arthritis encephalitis virus (CAEV) and equine dermis cells from infection by equine infectious anemia virus (EIAV). The characteristics of this inhibition against these lentiviruses are similar to those previously described for the inhibition of HIV-1 in ATH8 cells [17]. Thus, the 28-mer homo-oligomer of cytidine [S-(dC)28] was at least as effective as three anti-sense sequences targeted to the LTR,gag, andenv regions of CAEV. The effectiveness of homo-oligomers of equal length was in the order C>>A>T, and a random 28-copolymer with a composition of 2C:1G was as effective as S-(dC)28. Shorter oligonucleotides were less effective (28>14>5 mers) for all base compositions tested. While replication of a simian type D retrovirus was inhibited by S-(dC)28, this compound did not inhibit the cytopathogenicity of two type C retroviruses, amphotropic murine leukemia virus (MuLV), and baboon endogenous virus, when they were tested in the same cell lines used to support the replication of lentiviruses. Southern blot analysis of the high molecular weight DNA of drug-treated CAEV-infected cells showed that S-(dC)28 was acting at or before the reverse transcription step. Our present data and the earlier finding that S-(dC)28 is a potent in vitro inhibitor of the MuLV reverse transcriptase [15] suggest that S-(dC)28 is acting very early in the replication cycle of these lentiviruses. Since MuLV reverse transcriptase is inhibited in vitro, but its replication is not blocked in permissive cells, our data suggest that the phosphorothioate oligonucleotides are preventing virus attachment.

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DOI: 10.1007/BF01309457


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<term>Animals</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Arthritis-Encephalitis Virus, Caprine (drug effects)</term>
<term>Arthritis-Encephalitis Virus, Caprine (physiology)</term>
<term>Betaretrovirus (drug effects)</term>
<term>Betaretrovirus (physiology)</term>
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<term>Gammaretrovirus (physiology)</term>
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<term>HIV-1 (physiology)</term>
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<term>Lentivirus (physiology)</term>
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<term>Leukemia Virus, Murine (physiology)</term>
<term>Oligonucleotides, Antisense (pharmacology)</term>
<term>Ovary</term>
<term>Skin</term>
<term>Species Specificity</term>
<term>Thionucleotides</term>
<term>Virus Replication (drug effects)</term>
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<term>Animaux</term>
<term>Antiviraux (pharmacologie)</term>
<term>Betaretrovirus ()</term>
<term>Betaretrovirus (physiologie)</term>
<term>Cellules cultivées</term>
<term>Division cellulaire ()</term>
<term>Equus caballus</term>
<term>Femelle</term>
<term>Gammaretrovirus ()</term>
<term>Gammaretrovirus (physiologie)</term>
<term>Lentivirus ()</term>
<term>Lentivirus (physiologie)</term>
<term>Oligonucléotides antisens (pharmacologie)</term>
<term>Ovaire</term>
<term>Peau</term>
<term>Réplication virale ()</term>
<term>Spécificité d'espèce</term>
<term>Thionucléotides</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
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<term>Oligonucléotides antisens</term>
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<term>Gammaretrovirus</term>
<term>Lentivirus</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
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<term>HIV-1</term>
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<term>Acad</term>
<term>Amphotropic strain</term>
<term>Analog</term>
<term>Anemia virus</term>
<term>Animals</term>
<term>Antiviral</term>
<term>Antiviral activity</term>
<term>Antiviral effect ofphosphorothioate oligonucleotides</term>
<term>Archambault</term>
<term>Assay</term>
<term>Base composition</term>
<term>Caev</term>
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<term>Caprine arthritis encephalitis virus</term>
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<term>Cell culture supernatants</term>
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<term>Mitogenic assay</term>
<term>Mitogenic indices</term>
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<term>Natl</term>
<term>Normal oligonucleotides</term>
<term>Nuclease digestion</term>
<term>Oligodeoxynucleotides</term>
<term>Oligonucleotide</term>
<term>Oligonucleotide analogs</term>
<term>Oligonucleotides</term>
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<term>Phosphorothioate</term>
<term>Phosphorothioate analogs</term>
<term>Phosphorothioate oligodeoxynucleotides</term>
<term>Phosphorothioate oligonucleotides</term>
<term>Present data</term>
<term>Proc</term>
<term>Proc natl acad</term>
<term>Protease inhibitors</term>
<term>Replication</term>
<term>Retrovirus</term>
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<term>Serial dilutions</term>
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<term>Species Specificity</term>
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<term>Tahr cells</term>
<term>Tahr ovary cells</term>
<term>Test compounds</term>
<term>Thionucleotides</term>
<term>Thymus cells</term>
<term>Transcriptase</term>
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<term>Viral genome</term>
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<term>Virus absorption period</term>
<term>Virus attachment</term>
<term>Virus inoculum</term>
<term>Virus replication</term>
<term>Virus titer</term>
<term>Weeks post infection</term>
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<keywords scheme="MESH" xml:lang="fr">
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<term>Betaretrovirus</term>
<term>Cellules cultivées</term>
<term>Division cellulaire</term>
<term>Equus caballus</term>
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<front>
<div type="abstract" xml:lang="en">Summary: Phosphorothioate analogs of oligodeoxynucleotides at a concentration of 2µM protected Himalayan tahr cells from infection by caprine arthritis encephalitis virus (CAEV) and equine dermis cells from infection by equine infectious anemia virus (EIAV). The characteristics of this inhibition against these lentiviruses are similar to those previously described for the inhibition of HIV-1 in ATH8 cells [17]. Thus, the 28-mer homo-oligomer of cytidine [S-(dC)28] was at least as effective as three anti-sense sequences targeted to the LTR,gag, andenv regions of CAEV. The effectiveness of homo-oligomers of equal length was in the order C>>A>T, and a random 28-copolymer with a composition of 2C:1G was as effective as S-(dC)28. Shorter oligonucleotides were less effective (28>14>5 mers) for all base compositions tested. While replication of a simian type D retrovirus was inhibited by S-(dC)28, this compound did not inhibit the cytopathogenicity of two type C retroviruses, amphotropic murine leukemia virus (MuLV), and baboon endogenous virus, when they were tested in the same cell lines used to support the replication of lentiviruses. Southern blot analysis of the high molecular weight DNA of drug-treated CAEV-infected cells showed that S-(dC)28 was acting at or before the reverse transcription step. Our present data and the earlier finding that S-(dC)28 is a potent in vitro inhibitor of the MuLV reverse transcriptase [15] suggest that S-(dC)28 is acting very early in the replication cycle of these lentiviruses. Since MuLV reverse transcriptase is inhibited in vitro, but its replication is not blocked in permissive cells, our data suggest that the phosphorothioate oligonucleotides are preventing virus attachment.</div>
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