The Synergistic Inhibition of HIV-1 With Nucleoside Analogs Combined With A Natural Product, Resveratrol
C. DAVIS*, A. HEREDIA, and R. REDFIELD.
Inst. of Human Virology, Baltimore, MD
We evaluated the anti-HIV activity of a natural product, resveratrol (RV), combined with nucleoside analogs because of its effects to prolong S phase and its inhibition of ribonucleotide reductase.
Methods: The anti-HIV-1 effects of RV plus nucleoside analogs was assessed in peripheral blood mononuclear cells (PBMCs) stimulated with PHA and infected with HIV-1IIIb, clinical, and resistant isolates; in monocyte-derived macrophages (MDMs) infected with the macrophage-tropic isolate, HIV-1SF162; and in a resting T-lymphocytes assay infected with HIV-1IIIb. Cellular proliferation was measured by commercial MTT assay.
Results: RV synergistically enhanced the anti-HIV-1 activity of the nucleoside analogs ddI, zalcitabine (ddC), and zidovudine (AZT). 10 ÁM RV combined with 2 ÁM ddI, resulted in a 200 fold increase in antiviral activity. The addition of RV resulted in a greater than 10-fold augmentation of ddI-antiviral activity in infected MDMs. In a resting cell model of T-lymphocytes infection, RV plus ddI in combination, but not individually, suppressed the establishment of a productive viral infection. In addition, RV plus ddI markedly inhibited the replication of two ddI-resistant viral isolates, one containing the L74V reverse transcriptase (RT) gene mutation, the other containing 4 different resistance-associated mutations in the RT gene. Finally, when compared to HU, both 100 ÁM HU and 10 ÁM RV showed similar enhancement of ddI-antiviral suppressive activity. However, RV was shown to have less of a cellular anti-proliferative effect than HU.
Conclusion: These results highlight the strategy that targeting cellular enzymes and cell-cycle replication may be an effective means of inhibiting viral replication, both, in susceptible and resistant isolates of HIV-1. The clinical evaluation of resveratrol in the treatment of HIV infection warrants further investigation.
Key Words: Resveratrol, Ribonucleotide, S phase