Abstract
APOBEC3G is a member of the human cytidine deaminase family that restricts Vif-deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC50 values ranged from 0.106 μM to 7.987 μM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection.
Highlights
Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS)
These results indicated that hop-8 is a broad-spectrum inhibitor of HIV that efficiently inhibits lab-adapted, drug-resistant, clinically isolated strains of HIV-1 in different subtypes as well as HIV-2 with low cytotoxicity
After incubating for 3 days (PBMCs for 7 days), cell viability was determined by using the MTT assay, and the concentration required for 50% cytotoxicity (CC50 ) was determined
Summary
Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV auxiliary protein interactions have become novel targets for the design and development of potential anti-HIV apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) to suppress viral drugs. HIV factor replication efficiently by incorporating into in HIVthe infection, inhibits A3G through proteasome-mediated andof degradation-independent newly assembled virions and inducing. A3G’s highly efficient interruption of HIV-1 replication, Phorbol is a natural, plant-derived organic compound that belongs to the tigliane family of upregulating A3G expression provides a potential method for restricting wild-type HIV-1 replication. The and discovery non-tumorigenic phorbol esters (12-deoxyphorbol-13-acetate) tumorigenic phorbol esters prostratin and DPP (12-deoxyphorbol-13(12-deoxyphorbol-13-phenylacetate) that inhibit HIV replication in vitro opens up the possibilities phenylacetate) that inhibit HIV replication in vitro opens up the possibilities for their clinical use [43,44,45].
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