Variation in cell associated unspliced HIV RNA on antiretroviral therapy is associated with the circadian regulator BMAL-1

Christina Catherine Chang, Vivek Naranbhai, Jared Stern, Michael John Roche, Ashanti Dantanarayana, Ruian Ke, Surekha Tennakoon, Ajantha Solomon, Rebecca Hoh, Wendy Hartogensis, Frederick M. Hecht, Ken Sikaris, David J Price, Julian Elliott, Steven G Deeks, Melissa Churchill, Paul Cameron, Nicolas Hengartner, Alan S Perelson, Sharon Ruth Lewin

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Abstract

Objective(s): To determine whether variation in cell associated (CA) unspliced (US) HIV RNA in HIV-infected individuals on antiretroviral therapy (ART) has a circadian basis. Methods: Prospective observational study of HIV-infected individuals on ART. Blood was collected on three occasions and CA-US HIV RNA and mRNA of the Circadian-locomotor-output-cycles-kaput (CLOCK)-associated genes quantified by real time PCR. CLOCK-associated proteins were over expressed in a cell line stably transfected with an HIV long terminal repeat (LTR) luciferase reporter. Results: Using a mixed effects model, there was a significant increase in log-CA-US RNA at the third visit compared to the first visit (effect size of 0.619 with standard error (SE) of 0.098, p < 0.001) and an independent effect of time of blood draw (effect size 0.051, (SE 0.025), p = 0.040). The CLOCK-associated gene, Brain-and-muscle-ARNT-like-1 (BMAL-1) had a significant relationship with log CA-US HIV RNA (effect size 8.508 (SE 3.777), p = 0.028) and also with time (p = 0.045). Over expression of BMAL-1 and CLOCK in a cell line stably transfected with an HIV-LTR luciferase reporter resulted in an increase in luciferase expression and this was reduced following mutation of the second E-box in the HIV-LTR. Conclusions: The basal level of HIV transcription on ART can vary significantly and is modulated by the circadian regulator BMAL-1, amongst other factors.
Original languageEnglish
Pages (from-to)2119-2128
Number of pages10
JournalAIDS
Volume32
Issue number15
DOIs
Publication statusPublished - Sep 2018

Cite this

Chang, C. C., Naranbhai, V., Stern, J., Roche, M. J., Dantanarayana, A., Ke, R., Tennakoon, S., Solomon, A., Hoh, R., Hartogensis, W., Hecht, F. M., Sikaris, K., Price, D. J., Elliott, J., Deeks, S. G., Churchill, M., Cameron, P., Hengartner, N., Perelson, A. S., & Lewin, S. R. (2018). Variation in cell associated unspliced HIV RNA on antiretroviral therapy is associated with the circadian regulator BMAL-1. AIDS, 32(15), 2119-2128. https://doi.org/10.1097/QAD.0000000000001937