1. Targeting host nucleotide biosynthesis with resveratrol inhibits emtricitabine-resistant HIV-1
- Author
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Heredia, Alonso, Davis, Charles, Amin, Mohammed N, Le, Nhut M, Wainberg, Mark A, Oliveira, Maureen, Deeks, Steven G, Wang, Lai-Xi, and Redfield, Robert R
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,HIV/AIDS ,Genetics ,Complementary and Integrative Health ,Sexually Transmitted Infections ,Infection ,Anti-HIV Agents ,Cells ,Cultured ,Deoxycytidine ,Drug Resistance ,Viral ,Emtricitabine ,Enzyme-Linked Immunosorbent Assay ,HIV Core Protein p24 ,HIV Reverse Transcriptase ,HIV-1 ,Humans ,Lymphocytes ,Mutation ,Missense ,Real-Time Polymerase Chain Reaction ,Resveratrol ,Stilbenes ,Virus Replication ,antiretroviral therapy ,cytosine analogs ,drug resistance ,emtricitabine ,M184V mutation ,nucleoside analog reverse transcriptase inhibitors ,resource-limited setting ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Virology ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectiveThe M184V mutation in the HIV-1 reverse transcriptase gene is frequent (>50%) in patients, both in resource-rich and resource-limited countries, conferring high-level resistance (>100-fold) to the cytosine analog reverse transcriptase inhibitors lamivudine and emtricitabine. The reverse transcriptase enzyme of M184V HIV-1 mutants has reduced processivity, resulting in reduced viral replication, particularly at low deoxynucleotide (dNTP) levels. We hypothesized that lowering intracellular dNTPs with resveratrol, a dietary supplement, could interfere with replication of M184V HIV-1 mutants.Design and methodsEvaluation of the activity of resveratrol on infection of primary peripheral blood lymphocytes by wild-type and M184V mutant HIV-1. We assayed both molecular clones and primary isolates of HIV-1, containing M184V alone and in combination with other reverse transcriptase mutations. Viral infection was quantified by p24 ELISA and by quantitative real-time PCR analysis. Cell viability was measured by colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays.ResultsIn virus-infectivity assays, resveratrol did not inhibit replication of wild-type NL4-3 (resveratrol EC50 > 10 μmol/l), but it inhibited NL4-3 184V mutant (resveratrol EC50 = 5.8 μmol/l). These results were confirmed by real-time PCR analysis of early and late products of reverse transcription. Resveratrol inhibited molecular clones and primary isolates carrying M184V, alone or in combination with other reverse transcriptase mutations (resveratrol EC50 values ranging from 2.5 to 7.7 μmol/l).ConclusionsResveratrol inhibits HIV-1 strains carrying the M184V mutation in reverse transcriptase. We propose resveratrol as a potential adjuvant in HIV-1 therapy, particularly in resource-limited settings, to help control emtricitabine-resistant M184V HIV-1 mutants.
- Published
- 2014