Synergistic inhibition of HIV-1 in activated and resting peripheral blood mononuclear cells, monocyte-derived macrophages, and selected drug-resistant isolates with nucleoside analogues combined with a natural product, resveratrol

Resveratrol (trans-3,5,4'-trihydroxystilbene) is a phytoalexin present in g rapes, wine, and certain plants, which has recently been reported to posses s properties that may protect against atherosclerosis, certain cancers, and inflammation. We now report that resveratrol (RV) synergistically enhances the anti-HIV-1 activity of the nucleoside analogues zidovudine (AZT), zalc itabine (ddC), and didanosine (ddI). RV at 10 muM was not toxic to cells, a nd by itself reduced viral replication by 20% to 30%. In phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMCs) infected with H TLV-IIIB, 10 muM RV reduced the 90 % inhibitory concentration (IC,,) of AZT , ddC, and ddI by 3.5-, 5.5-, and 17.8-fold, respectively. Similar antivira l activity was demonstrated when ddI was combined with 5 or 10 mM RV in PBM Cs infected with clinical isolates of HIV-1. The addition of RV resulted in a >10-fold augmentation of ddI-antiviral activity in infected monocyte-der ived macrophages (MDMs). In a resting cell model of T lymphocytes which wer e infected with HTLV-IIIB, RV plus ddI in combination, but not individually , suppressed establishment of a productive viral infection. In addition, RV plus ddI markedly inhibited the replication of four ddI-resistant viral is olates, three of which presented mutations in the RT gene conferring RT-mul tidrug resistance. Finally, when compared with hydroxyurea (HU), both 100 m M HU and TO mM RV showed similar enhancement of ddI-antiviral suppressive a ctivity. However, RV was shown to have less of a cellular antiproliferative effect than HU.