Targeting host nucleotide biosynthesis with resveratrol inhibits emtricitabine-resistant HIV-1

Heredia, Alonsoa; Davis, Charlesa; Amin, Mohammed N.a; Le, Nhut M.a; Wainberg, Mark A.b; Oliveira, Maureenb; Deeks, Steven G.c; Wang, Lai-Xia; Redfield, Robert R.a

AIDS:
doi: 10.1097/QAD.0000000000000168
Basic Science: Concise Communications
Abstract

Objective: The 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 methods: Evaluation 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.

Results: In 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).

Conclusions: Resveratrol 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-1mutants.

Author Information

aInstitute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA

bMcGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada

cSan Francisco VA Medical Center and University of California, San Francisco, California, USA.

Correspondence to Alonso Heredia, Institute of Human Virology, 725 W. Lombard St, Baltimore, MD 21201, USA. Tel: +1 410 7064594; fax: +1 410 7064992; e-mail: aheredia@ihv.umaryland.edu

Received 15 August, 2013

Revised 27 November, 2013

Accepted 27 November, 2013

© 2014 Lippincott Williams & Wilkins, Inc.