Synergistic antiviral effect of PEG-asparaginase (ONCASPAR), with protease inhibitor alone and in combination with RT inhibitors against HIV-1 infected T-cells: a model of HIV-1-induced T-cell lymphoma.
We evaluated the anti-HIV-1 activity of the T-cell-specific protein inhibitor PEG-asparaginase (PEG-ASNase) in human HIV-1-infected T-cells. We further examined the drug synergism between PEG-ASNase and the protease inhibitor Saquinavir (SAQ), both alone and in combination with nucleoside analog reverse transcriptase inhibitors (NRTI). Our drug synergism studies served as a model for an HIV-induced T-cell lymphoma. Phytohemagglutinin [PHA(+)] stimulated T-cells were infected with HIV-1 and then treated with one or more drugs 90 minutes from the viral exposure. To measure inhibition of viral replication, we examined HIV-1 RT and HIV-1 RNA in the supernatant and intracellularly on day 7 post-infection and drug treatment. Last, we examined the effect of administering drugs immediately after HIV-1 infection of T-cells to simulate treatment after an accidental exposure to the virus. PEG-ASNase, even when used alone, has anti-HIV-1 activity in PHA(+)-stimulated T-cells due to inhibition of protein synthesis. When the drug was used with SAQ, the combination was synergistic in inhibiting HIV-1 RT and RNA in the supernatant and intracellularly by 2.5 log10 in comparison with controls. PEG-ASNase and SAQ were even more effective in inhibiting HIV-1 replication when combined with the NRTI inhibitors azidothymidine (AZT) and (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). The addition of ribonucleotide reductase inhibitor, 2-methyl-1H-isoindole-1,3-dione (MISID), further potentiated the antiviral effect of the regimen. HIV-1 RT and RNA analyses showed that the administration of the PEG-ASNase + SAQ drug combination immediately following exposure to HIV-1 completely inhibited the infection of T-cells in our in vitro T-cell model. From these results we conclude that PEG-ASNase is a valuable T-cell-specific protein inhibitor against HIV-1 infection, when used singly or in combination with a protease inhibitor, an RT inhibitor and an RR inhibitor. Since PEG-ASNase is a drug of choice for the treatment of T-cell lymphomas, a combination regimen containing PEG-ASNase could be very effective in the treatment of HIV-1-induced T-cell lymphoma and possibly AIDS. Future studies are needed in HIV-infected and/or HIV-induced T-cell lymphoma patients to investigate these findings.
Avramis
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Division of Hematology/Oncology, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA. vavramis@chla.usc.edu
Kwock
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Avramis
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Cohen
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Inderlied
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D001215:Asparaginase / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D016399:Lymphoma, T-Cell / Q000821:virology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000821:virology*; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000494:pharmacology
C121190:6-methyl-2-isopropylsulfonyloxy-1(H)-isoindole-1,3-dione; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D007211:Indoles; D054833:Isoindoles; D018894:Reverse Transcriptase Inhibitors; D011092:Polyethylene Glycols; D015215:Zidovudine; C042705:pegaspargase; D054303:HIV Reverse Transcriptase; D001215:Asparaginase; D019258:Saquinavir