Cannabinoid and HIV / Septiembre

Cannabinoids and HIV

Characterization of non-olfactory GPCRs in human sperm with a focus on GPR18.

Flegel C(1), Vogel F(1,)(2), Hofreuter A(1), Wojcik S(1), Schoeder C(3), Kieć-Kononowicz K(4), Brockmeyer NH(5,)(6), Müller CE(3), Becker C(7), Altmüller J(7), Hatt H(1), Gisselmann G(1).

> Author information:

(1)Ruhr-University Bochum, Department of Cell Physiology, Bochum, Germany. (2)Department of Dermatology, Venerology, and Allergology, University Hospital Essen, University of Duisburg-Essen, Germany. (3)Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Universität Bonn, Bonn, Germany. (4)Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, PL-30-688 Kraków, Poland. (5)Competence Network for HIV/AIDS, Ruhr University Bochum, Bochum, Germany. (6)Department of Dermatology, Venerology, and Allergology, Center for sexuell health, Ruhr University Bochum, Bochum, Germany. (7)University of Köln, Cologne Center for Genomics, Köln, Germany.

G protein-coupled receptors (GPCRs) transduce external chemical cues into intracellular signals and are involved in a plethora of physiological processes, but knowledge regarding the function of these receptors in spermatozoa is limited. In the present study, we performed RNA-Seq and analyzed the expression of the all GPCRs except olfactory receptors in human spermatozoa. We revealed the expression of up to 223 different GPCR transcripts in human spermatozoa (FPKM > 0.1) and identified GPR18, a newly described cannabinoid receptor, together with GPR137 and GPR135, as one of the three most highly expressed GPCRs.

To date, the expression of GPR18 was completely unknown in human spermatozoa. We confirmed GPR18 expression using RT-PCR and immuncytochemistry experiments and localized the GPR18 protein in the midpiece of human spermatozoa. Stimulation of human spermatozoa with the GPR18 ligand N-arachidonoylglycine induced the phosphorylation of 12 protein kinases, some of them are for example known to be involved in the acrosome reaction. In line with this, N-arachidonoylglycine affected the cytoskeleton by changing levels of F-actin and inducing the acrosome reaction in human spermatozoa in a concentration-dependent manner. Our results indicate that GPR18 might be involved in physiological processes of human spermatozoa, suggesting GPR18 to be a potential player in sperm physiology.

Efficacy and safety of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic HCV genotype 1 infection receiving opioid substitution therapy: Analysis of Phase 3 ION trials. Grebely J(1), Mauss S(2), Brown A(3), Bronowicki JP(4), Puoti M(5), Wyles D(6), Natha M(7), Zhu Y(7), Yang J(7), Kreter B(7), Brainard DM(7), Yun C(7), Carr V(8), Dore GJ(1).


> Author information:

(1)The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia. (2)Center for HIV and Hepatogastroenterology, Düsseldorf, Germany. (3)Liver Unit, Department of Medicine, St Mary's Hospital, London, United Kingdom. (4)Hépato-gastroentérologie, INSERM U954, CHU Nancy, France. (5)Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milan, Italy. (6)Division of Infectious Diseases, University of California, San Diego, USA. (7)Gilead Sciences, Foster City, USA. (8)Gilead Sciences, Stockley Park, United Kingdom.

> BACKGROUND: Interferon-based HCV therapy is safe and effective among people receiving opioid substitution therapy (OST), but treatment uptake remains low. The aim of this post-hoc analysis was to evaluate the impact of OST and drug use during therapy on completion, adherence, sustained virologic response (SVR12) and safety of ledipasvir/sofosbuvir±ribavirin.

> METHODS: The Phase 3 ION studies evaluated a fixed-dose combination of ledipasvir/sofosbuvir±ribavirin administered for 8/12/24 weeks in patients with chronic HCV genotype 1. People with clinically significant drug use (prior 12 months) or non-cannabinoids detected at screening by urine drug tests (not explained by prescriptions) were ineligible. Stored samples were available from ION-1 for retrospective testing for illicit drugs by ELISA.

> RESULTS: Among 1952 patients enrolled in the ION studies, 4% (n=70) were receiving OST. Among those receiving (n=70) and not receiving OST (n=1882), there was no difference in treatment completion (97% vs 98%, P=0.40) ≥80% adherence (93% vs 92%, P=1.00), SVR12 (94% vs 97%, P=0.28), and serious AEs (4% vs 3%, P=0.43), respectively. Among participants in the ION-1 trial, 23% (n=196) used illicit drugs during therapy (15% cannabinoids alone; 8% other illict drugs±cannabinoids). There was no difference in treatment completion, ≥80% adherence, SVR12 or serious AEs in those with no drug use during treatment compared with those who used cannabinoids and/or other illicit drugs. No cases of HCV reinfection were observed in the 24 weeks following treatment.

> CONCLUSIONS: OST and drug use during HCV therapy did not impact treatment completion, adherence, SVR12 or safety.


© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.