Journal Article

Targeting of the Purine Biosynthesis Host Cell Pathway Enhances the Activity of Tenofovir Against Sensitive and Drug-Resistant HIV-1

Alonso Heredia, Charles E. Davis, Marvin S. Reitz, Nhut M. Le, Mark A. Wainberg, James S. Foulke, Lai-Xi Wang and Robert R. Redfield

in The Journal of Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 208, issue 12, pages 2085-2094
Published in print December 2013 | ISSN: 0022-1899
Published online August 2013 | e-ISSN: 1537-6613 | DOI: https://dx.doi.org/10.1093/infdis/jit395
Targeting of the Purine Biosynthesis Host Cell Pathway Enhances the Activity of Tenofovir Against Sensitive and Drug-Resistant HIV-1

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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.

Keywords: HIV-1; antiretrovirals; drug resistance; NRTI; tenofovir; subtype C; resveratrol

Journal Article.  5391 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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