Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jan;20(2):105-111.
doi: 10.2217/pgs-2018-0140. Epub 2019 Jan 10.

Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir

Allyson N Hamlin  1 , Joseph Tillotson  1 , Namandjé N Bumpus  1
Affiliations
Review

Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir

Allyson N Hamlin et al. Pharmacogenomics. 2019 Jan.

Abstract

As antiretroviral therapy has become more accessible across the world and coformulations have improved patient compliance; the morbidity and mortality of HIV/AIDS has decreased. However, there is still a substantial gap in knowledge regarding the impact of genetic variation on the metabolism of and response to some of the most commonly prescribed antiretrovirals, including the nucleotide reverse transcriptase inhibitor tenofovir. While it has been scientifically established that tenofovir must be activated to be efficacious against HIV, the enzymes responsible for this activation have not been well characterized. The purpose of this review is to summarize and clarify the scientific knowledge regarding the enzymes that phosphorylate and activate this clinically important drug.

Keywords: HIV; antiretroviral therapy; drug metabolism; genetic variants; precision medicine.

PubMed Disclaimer

Conflict of interest statement

Financial & competing interests disclosure

This work was supported by NIH (grant numbers R01 AI128781, UM1 AI068613 and UM1 AI106707). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Schematic of the intracellular phosphorylation of TFV.
TFV requires two sequential phosphorylation steps to become a pharmacologically active triphosphate analogue, denoted as TFV-DP. Lade et al. [19] discovered that AK2 can catalyze the phosphorylation of TFV to TFV-MP in peripheral blood mononuclear cells, vaginal, and colorectal tissues. In addition, PKM and PKLR were found to catalyze the phosphorylation of TFV-MP to TFV-DP in peripheral blood mononuclear cells and vaginal tissue, while CKM phosphorylated TFV-MP to TFV-DP in colorectal tissue. AK2: Adenylate kinase 2; CKM: Creatine kinase muscle; DP: Diphosphate; MP: Monophosphate; PKM: Pyruvate kinase muscle; PKLR: Pyruvate kinase liver and red blood cell; TFV: Tenofovir.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Crum NF, Riffenburgh RH, Wegner S, et al. Comparisons of causes of death and mortality rates among HIV-infected persons: analysis of the pre-, early, and late HAART (highly active antiretroviral therapy) eras. J. Acquir. Immune Defic. Syndr. 2006;41(2):194–200. - PubMed
    1. Jenh AM, Thio CL, Pham PA. Tenofovir for the treatment of hepatitis B virus. Pharmacotherapy. 2009;29(10):1212–1227. - PubMed
    1. Masho SW, Wang CL, Nixon DE. Review of tenofovir–emtricitabine. Ther. Clin. Risk Manag. 2007;3(6):1097–1104. - PMC - PubMed
    1. Gallant JE, Dejesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N. Engl. J. Med. 2006;354(3):251–260. - PubMed
    1. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J. Acquir. Immune Defic. Syndr. 2010;53(3):323–332. - PubMed

Publication types

MeSH terms