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Journal of AIDS & Clinical Research

ISSN: 2155-6113

Open Access

Synergistic Inhibition of HIV-1 Replication by a Combination of Viral Inhibitors Isolated from Compounds Targeting Viral Entry, Integration and Proviral Transcription of Clinical Isolates and Drug-resistant Strains

Abstract

Ibrahim S. Abd-Elazem, Kiattisak Lugsanangarm, Nadtanet Nunthaboot and Ru Chih C. Huang*

Background: Drug resistance associated with HIV-1 variants emerges due to undetected treatment failures. Therefore, it is urgent to search for an antiretroviral therapy to control HIV replication. We examined the synergistic inhibition of HIV-1 replication by a combination of potential inhibitors against clinical isolates and drug-resistant strains.

Methods: Nontoxic, natural product-derived inhibitors, the viral entry inhibitor (Gen-1 (tieghemelin, a triterpenoid saponin)), the integrase inhibitor (M522 (lithospermic acid)), and the transcription inhibitors (G4N (tetraglycylated NDGA) or M4N (tetra-O-methyl-NDGA, terameprocol)) were used to target viral entry, integration, and transcription steps. They have been tested against the replication of an AZT-resistant strain of HIV-1 and clinical isolates from HIV-infected patients, where they were examined alone and, in their combinations, to inhibit HIV replication in human H9 cells and PBMCs. The binding conformations and important interactions of all these inhibitors have been evaluated by molecular docking studies.

Results: The IC50 values for Gen-1, M522, and G4N were 20.0 μM, 2.2 μM, and 14.0 μM, respectively, when tested individually, while in combination, it was 1.2 μM when tested in HIV-1RTMF (AZT-resistant strain) infected PBMCs, whereas 65.0 μM, 18.0 μM, and 27.0 μM individually and in combination, it was 3.0 μM when tested against the clinical isolate. The effectiveness of the three inhibitors in combination was evaluated using the calculation of the combination index, where strong synergy was observed for the three inhibitors across all effect levels. Molecular docking calculations revealed that all inhibitors can bind and form chemical interactions via H-bond, π…π interaction, and hydrophobic interaction with the corresponding target.

Conclusion: We concluded that the targeted three-drug combination effectively blocked three steps of the life cycle of HIV-1 and prevented viral entry, integration, and transcription processes of the virus with high efficacy, which exhibited potent synergistic drug activities without any toxicity.

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