Targeting of the purine biosynthesis host cell pathway enhances the activity of tenofovir against sensitive and drug-resistant HIV-1.

Global programs expanding access to antiretroviral treatments represent a highly successful public health intervention [1]. To date, >6 million persons living with human immunodeficiency virus type 1 (HIV-1) infection have received antiviral treatment. The continued expansion and sustainability of these important programs depend on maintaining the technical feasibility of affordable and scalable antiretroviral agents to be preserved [2]. Not all antiretroviral drugs have the necessary product profile for wide-scale application. Early programs relied heavily on the use of thymidine analogs, zidovudine (AZT) or stavudine (D4T), driven by cost considerations. In addition, in the resource-limited setting, assessment of treatment outcomes was based on the clinical definition of treatment failure. As a result, patients experienced subclinical viral failure and accumulated multiple thymidine analog mutations (TAMs) that convey drug resistance to the nucleoside/nucleotide analog reverse transcriptase inhibitor (NRTI) background of currently World Health Organization–recommended second-line regimens. As such, the second-line antiretroviral regimen efficacy is limited [3]. Targeting host-cell pathways important in nucleoside biosynthesis is a strategy of potential clinical relevance, particularly as it relates to the long-term technical feasibility of ongoing global antiretroviral treatment programs and to maintaining efficacy of nucleoside/nucleotide analogs. Previous work has shown that targeting cellular ribonucleotide reductase, which catalyzes synthesis of dNTPs, with hydroxyurea enhances the anti-HIV activities of NRTIs, including drug-resistant strains [4–6]. However, potential toxicity has limited the use of hydroxyurea in HIV-1 patients. Safer inhibitors of ribonucleotide reductase are currently being investigated against HIV-1 [7, 8]. Resveratrol (3,4′,5-trihydroxystillbene), a natural compound from grapes and other fruits, is an inhibitor of ribonucleotide reductase that preferentially lowers dATP levels and prolongs the S phase of the cell cycle [9–11], activities that may enhance nucleoside analog utilization. Resveratrol has various potential benefits to health, but it is currently unclear whether dietary concentrations are sufficient to promote them (reviewed in [12]). Resveratrol's presence in red wine has been proposed to explain the French Paradox, a reduced risk of cardiovascular diseases in French people despite consumption of a fat-rich diet [13]. Animal studies suggest that resveratrol administration can indeed help prevent coronary heart diseases, as well as diabetes and several types of cancer (reviewed in [14]). We have previously demonstrated synergistic inhibition of HIV-1 by combinations of resveratrol and first-generation nucleoside analogs and restoration of drug susceptibility in isolates resistant to nucleoside analogs [15, 16]. Similar results with other nucleoside analogs have been reported by others [17]. In this study, we have evaluated the effects of resveratrol on the antiviral activity of the adenosine analog tenofovir (TFV), the most commonly used NRTI and a key drug whose sustained efficacy will be central to long-term impact of global antiretroviral treatment programs.