Tenofovir Activating Kinases May Impact the Outcome of HIV Treatment and Prevention

Tenofovir (TFV), an acyclic nucleoside phosphonate analogue of 2′deoxyadenosine, remains a first-line choice for the treatment of HIV infections under its prodrug form (i.e. tenofovir disoproxil fumarate, TDF). During the last decade, the use of TFV in pre-exposure prophylaxis (PrP) was first investigated as a vaginal microbicide gel (Mayer et al., 2006). More recently, rectal microbicide preparations and oral TDF alone or in combination with emtricitabine have been evaluated in PrP (Marrazzo et al., 2015), opening a new era in the fight against HIV. Clinical studies using TFV-based regimens in PrP provided inconsistent results, which have been primarily explained by poor adherence. The study by Lade et al. (2015) explored whether differences in the mechanism of TFV activation in peripheral blood mononuclear cells (PBMCs), vaginal and colorectal tissues exist. Also, they examined whether genetic variation in the nucleotide kinases that activate the drug could be responsible for the discrepant results observed in PrP studies using TFV-based regimens. To be active, TFV requires two successive phosphorylation catalyzed by cellular kinases. Then, its active diphosphate form (TFV-DP) targets the HIV reverse transcriptase leading to inhibition of viral replication. The first step of TFV activation is substrate-specific and requires phosphorylation by a cellular adenylate kinase (AK). The isoform AK2 is known to be localized in the mitochondrial intermembrane space and to catalyze TFV phosphorylation in a more efficient manner than its cytoplasmic counterpart AK1. Lade et al. (2015) found that AK2 activates TFV to TFV-MP in PBMCs and vaginal and colon tissues from healthy, HIV-uninfected donors that