Identifying Risk of Viral Failure in Treated HIV-Infected Patients Using Different Measures of Adherence: The Antiretroviral Therapy Cohort Collaboration

Adherence to antiretroviral therapy (ART) is critical for successful treatment of Human Immunodeficiency Virus (HIV), but comparisons across settings are difficult because adherence is measured in different ways. We examined utility of different adherence measures for identification of patients at risk of viral failure (VF). Eight cohorts in the ART Cohort Collaboration contributed data from pharmacy refills or self-report questionnaires collected between 1996 and 2013 (N = 11689). For pharmacy data (N = 7156), we examined associations of percentage adherence during the 1st year of ART with VF (>500 copies/mL) at 1 year. For self-report data (N = 4533), we examined 28-day adherence with VF based on closest viral load measure within 6 months after questionnaire date. Since adherence differed markedly by measurement type, we defined different cut-off points for pharmacy (lowerOther UBCNon UBCReviewedFacult

Identification of intracellular carriers for the endocannabinoid anandamide

The endocannabinoid anandamide (arachidonoyl ethanolamide, AEA) is an uncharged neuromodulatory lipid that, similar to many neurotransmitters, is inactivated through its cellular uptake and subsequent catabolism. AEA is hydrolyzed by fatty acid amide hydrolase (FAAH), an enzyme localized on the endoplasmic reticulum. In contrast to most neuromodulators, the hydrophilic cytosol poses a diffusional barrier for the efficient delivery of AEA to its site of catabolism. Therefore, AEA likely traverses the cytosol with the assistance of an intracellular carrier that increases its solubility and rate of diffusion. To study this process, AEA uptake and hydrolysis were examined in COS-7 cells expressing FAAH restricted to the endoplasmic reticulum, mitochondria, or the Golgi apparatus. AEA hydrolysis was detectable at the earliest measurable time point (3 seconds), suggesting that COS-7 cells, normally devoid of an endocannabinoid system, possess an efficient cytosolic trafficking mechanism for AEA. Three fatty acid binding proteins (FABPs) known to be expressed in brain were examined as possible intracellular AEA carriers. AEA uptake and hydrolysis were significantly potentiated in N18TG2 neuroblastoma cells after overexpression of FABP5 or FABP7, but not FABP3. Similar results were observed in COS-7 cells stably expressing FAAH. Consistent with the roles of FABP as AEA carriers, administration of the competitive FABP ligand oleic acid or the selective non-lipid FABP inhibitor BMS309403 attenuated AEA uptake and hydrolysis by ≈50% in N18TG2 and COS-7 cells. Taken together, FABPs represent the first proteins known to transport AEA from the plasma membrane to FAAH for inactivation and may therefore be novel pharmacological targets