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Discovery of genetic variants of the kinases that activate tenofovir among individuals in the United States, Thailand, and South Africa: HPTN067

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Title: Discovery of genetic variants of the kinases that activate tenofovir among individuals in the United States, Thailand, and South Africa: HPTN067
Authors: Figueroa, Dominique B., Tillotson, Joseph, Li, Maoji, Piwowar-Manning, Estelle, Hendrix, Craig W., Holtz, Timothy H., Bokoch, Kevin, Bekker, Linda-Gail, van Griensven, Frits, Mannheimer, Sharon B., Hughes, James P., Grant, Robert M., Bumpus, Namandje N.
Publication Year: 2018
Collection: Columbia University: Academic Commons
Subject Terms: Phosphorylation, Antiviral agents, Human genetics--Variation, Biometry, Medicine
Description: Tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, requires two phosphorylation steps to form a competitive inhibitor of HIV reverse transcriptase. Adenylate kinase 2 (AK2) has been previously demonstrated to phosphorylate tenofovir to tenofovir-monophosphate, while creatine kinase, muscle (CKM), pyruvate kinase, muscle (PKM) and pyruvate kinase, liver and red blood cell (PKLR) each have been found to phosphorylate tenofovir-monophosphate to the pharmacologically active tenofovir-diphosphate. In the present study, genomic DNA isolated from dried blood spots collected from 505 participants from Bangkok, Thailand; Cape Town, South Africa; and New York City, USA were examined for variants in AK2, CKM, PKM, and PKLR using next-generation sequencing. The bioinformatics tools SIFT and PolyPhen predicted that 19 of the 505 individuals (3.7% frequency) carried variants in at least one kinase that would result in a decrease or loss of enzymatic activity. To functionally test these predictions, AK2 and AK2 variants were expressed in and purified from E. coli, followed by investigation of their activities towards tenofovir. Interestingly, we found that purified AK2 had the ability to phosphorylate tenofovir-monophosphate to tenofovir-diphosphate in addition to phosphorylating tenofovir to tenofovir-monophosphate. Further, four of the six AK2 variants predicted to result in a loss or decrease of enzyme function exhibited a ≥30% decrease in activity towards tenofovir in our in vitro assays. Of note, an AK2 K28R variant resulted in a 72% and 81% decrease in the formation of tenofovir-monophosphate and tenofovir-diphosphate, respectively. These data suggest that there are naturally occurring genetic variants that could potentially impact TFV activation.
Document Type: article in journal/newspaper
Language: English
Relation: https://doi.org/10.7916/D8D52454
DOI: 10.7916/D8D52454
Availability: https://doi.org/10.7916/D8D52454
Accession Number: edsbas.6E614272
Database: BASE
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  Data: Discovery of genetic variants of the kinases that activate tenofovir among individuals in the United States, Thailand, and South Africa: HPTN067
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  Data: <searchLink fieldCode="AR" term="%22Figueroa%2C+Dominique+B%2E%22">Figueroa, Dominique B.</searchLink><br /><searchLink fieldCode="AR" term="%22Tillotson%2C+Joseph%22">Tillotson, Joseph</searchLink><br /><searchLink fieldCode="AR" term="%22Li%2C+Maoji%22">Li, Maoji</searchLink><br /><searchLink fieldCode="AR" term="%22Piwowar-Manning%2C+Estelle%22">Piwowar-Manning, Estelle</searchLink><br /><searchLink fieldCode="AR" term="%22Hendrix%2C+Craig+W%2E%22">Hendrix, Craig W.</searchLink><br /><searchLink fieldCode="AR" term="%22Holtz%2C+Timothy+H%2E%22">Holtz, Timothy H.</searchLink><br /><searchLink fieldCode="AR" term="%22Bokoch%2C+Kevin%22">Bokoch, Kevin</searchLink><br /><searchLink fieldCode="AR" term="%22Bekker%2C+Linda-Gail%22">Bekker, Linda-Gail</searchLink><br /><searchLink fieldCode="AR" term="%22van+Griensven%2C+Frits%22">van Griensven, Frits</searchLink><br /><searchLink fieldCode="AR" term="%22Mannheimer%2C+Sharon+B%2E%22">Mannheimer, Sharon B.</searchLink><br /><searchLink fieldCode="AR" term="%22Hughes%2C+James+P%2E%22">Hughes, James P.</searchLink><br /><searchLink fieldCode="AR" term="%22Grant%2C+Robert+M%2E%22">Grant, Robert M.</searchLink><br /><searchLink fieldCode="AR" term="%22Bumpus%2C+Namandje+N%2E%22">Bumpus, Namandje N.</searchLink>
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  Data: 2018
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  Data: Columbia University: Academic Commons
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  Data: <searchLink fieldCode="DE" term="%22Phosphorylation%22">Phosphorylation</searchLink><br /><searchLink fieldCode="DE" term="%22Antiviral+agents%22">Antiviral agents</searchLink><br /><searchLink fieldCode="DE" term="%22Human+genetics--Variation%22">Human genetics--Variation</searchLink><br /><searchLink fieldCode="DE" term="%22Biometry%22">Biometry</searchLink><br /><searchLink fieldCode="DE" term="%22Medicine%22">Medicine</searchLink>
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  Data: Tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, requires two phosphorylation steps to form a competitive inhibitor of HIV reverse transcriptase. Adenylate kinase 2 (AK2) has been previously demonstrated to phosphorylate tenofovir to tenofovir-monophosphate, while creatine kinase, muscle (CKM), pyruvate kinase, muscle (PKM) and pyruvate kinase, liver and red blood cell (PKLR) each have been found to phosphorylate tenofovir-monophosphate to the pharmacologically active tenofovir-diphosphate. In the present study, genomic DNA isolated from dried blood spots collected from 505 participants from Bangkok, Thailand; Cape Town, South Africa; and New York City, USA were examined for variants in AK2, CKM, PKM, and PKLR using next-generation sequencing. The bioinformatics tools SIFT and PolyPhen predicted that 19 of the 505 individuals (3.7% frequency) carried variants in at least one kinase that would result in a decrease or loss of enzymatic activity. To functionally test these predictions, AK2 and AK2 variants were expressed in and purified from E. coli, followed by investigation of their activities towards tenofovir. Interestingly, we found that purified AK2 had the ability to phosphorylate tenofovir-monophosphate to tenofovir-diphosphate in addition to phosphorylating tenofovir to tenofovir-monophosphate. Further, four of the six AK2 variants predicted to result in a loss or decrease of enzyme function exhibited a ≥30% decrease in activity towards tenofovir in our in vitro assays. Of note, an AK2 K28R variant resulted in a 72% and 81% decrease in the formation of tenofovir-monophosphate and tenofovir-diphosphate, respectively. These data suggest that there are naturally occurring genetic variants that could potentially impact TFV activation.
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