Targeting of the purine biosynthesis host cell pathway enhances the activity of tenofovir against sensitive and drug-resistant HIV-1.
BACKGROUND
Targeting host-cell pathways to increase the potency of nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) is an important strategy for clinical investigation. Resveratrol is a natural product that inhibits cellular ribonucleotide reductase, prolonging the S phase of the cell cycle and preferentially lowering dATP levels.


METHODS
We performed in vitro evaluation of resveratrol on the antiviral activity of adenosine analog tenofovir (TFV) against sensitive and drug-resistant human immunodeficiency virus type 1 (HIV-1), from subtypes B and C, in primary cells.


RESULTS
Resveratrol enhanced the antiviral activity of TFV by up to 10-fold and restored susceptibility of TFV-resistant viruses. Resveratrol prevented wild-type HIV-1 from developing phenotypic resistance to TFV. Notably, resveratrol enhanced TFV activity against sensitive and resistant HIV-1 from both subtypes B and C.


CONCLUSIONS
Prolonged wide-scale use of thymidine analogs in the setting of viral failure has limited the efficacy of second-line NRTI-based regimens in Africa. Moreover, the extensive use of ddI and d4T has led to high frequencies of the K65R mutation, further compromising TFV efficacy. In light of increasing resistance to commonly used NRTIs in global HIV treatment programs, targeting nucleoside biosynthesis with resveratrol, or derivatives with improved bioavailabilities, is a potential strategy to maintain, enhance, and restore susceptibility of commonly used NRTIs.
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
Alonso
A
Heredia
Charles E
CE
Davis
Marvin S
MS
Reitz
Nhut M
NM
Le
Mark A
MA
Wainberg
James S
JS
Foulke
Lai-Xi
LX
Wang
Robert R
RR
Redfield
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology*; D011687:Purines / Q000096:biosynthesis* / Q000378:metabolism; D019713:Receptors, CCR5; D000077185:Resveratrol; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D000068698:Tenofovir; D014779:Virus Replication / Q000187:drug effects
C584933:CCR5 protein, human; D063065:Organophosphonates; D011687:Purines; D019713:Receptors, CCR5; D018894:Reverse Transcriptase Inhibitors; D013267:Stilbenes; D000068698:Tenofovir; D000225:Adenine; D000077185:Resveratrol
HIV-1; NRTI; antiretrovirals; drug resistance; resveratrol; subtype C; tenofovir