Previously unreported <i>AK2</i> missense variants detected in clinical trial participants located in Bangkok, Thailand, Cape Town, South Africa, and New York City, USA.

<p>Previously unreported <i>AK2</i> missense variants detected in clinical trial participants located in Bangkok, Thailand, Cape Town, South Africa, and New York City, USA.</p

Previously unreported <i>CKM</i> missense variants detected in clinical trial participants located in Bangkok, Thailand, Cape Town, South Africa, and New York City, USA.

<p>Previously unreported <i>CKM</i> missense variants detected in clinical trial participants located in Bangkok, Thailand, Cape Town, South Africa, and New York City, USA.</p

HPTN 067 participant enrollment location and gender information.

<p>HPTN 067 participant enrollment location and gender information.</p

Naturally occurring genetic variants of AK2 and the resulting impact on TFV phosphorylation.

<p>Wild-type (WT) AK2 and variants were expressed in and purified from <i>E</i>. <i>coli</i> in order to evaluate their effects on TFV phosphorylation in vitro. Proteins were incubated with 1 mM TFV in assay buffer for 2.5 h before reaction was quenched. A saturating concentration of TFV was used in order to ensure that substrate depletion would not play a causal role in differences observed in the formation of phosphates in these activity assays. TFV-MP and TFV-DP were detected by uHPLC-MS/MS where signal to noise ratio was used to establish the corresponding bar graph. Error bars represent standard deviation; n = 3. A two-tailed unpaired <i>t</i> test and significance was set as follows: *, p≤0.05; **, p≤0.01; ***, p≤0.001.</p

Previously unreported <i>PKLR</i> missense variants detected in clinical trial participants located in Thailand, South Africa, and the USA.

<p>Previously unreported <i>PKLR</i> missense variants detected in clinical trial participants located in Thailand, South Africa, and the USA.</p

Distribution of individuals enrolled at the Bangkok, Cape Town, and New York City study sites carrying genetic variants in TFV-activating kinases.

<p>Each rectangle is representative of a TFV-activating kinase that was sequenced: <i>AK2</i> in blue, <i>CKM</i> in pink, <i>PKM</i> in orange and <i>PKLR</i> in green. Numerical values indicate the number of individuals detected to carry a single nucleotide variation or deletion. Overlapping regions of each rectangle indicate the number of individuals with genetic variants in more than one kinase.</p