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Variation in cell-associated unspliced HIV RNA on antiretroviral therapy is associated with the circadian regulator brain-and-muscle-ARNT-like-1

Erratum

doi: 10.1097/01.aids.0000547779.98036.2d
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All figures in this article [1] were published in grayscale. These figures should instead be published in color as shown below:

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Fig. 1. Relationship of cell-associated unspliced HIV RNA in CD4+ T cells, visit and time of blood collection (n = 30).

Results from three time points collected from each participant are connected by a line. The color of the symbol denotes the preintervention time-point. These were prior to enrolling in the study [screening (B1; black)], immediately before the first dose of an intervention, here being disulfiram (B3; red), and a time-point between (B2; grey).

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Fig. 2. Relationship of circadian-locomotor-output-cycles-kaput-associated genes and visit.

Expression of CLOCK-associated genes in HIV-infected individuals on suppressive ART at three time-points (n = 30). Data were normalized to GAPDH expression level by the ΔΔCT method. The median and inter-quartile range are shown. Nominal P values from Wilcoxon matched pairs signed rank tests are shown for significant associations. The color of the symbol denotes the preintervention time-point. These were prior to enrolment [screening (B1; black)], immediately before the first dose of an intervention, here being disulfiram (B3; red), and a time-point between (B2; grey). ART, antiretroviral therapy; CLOCK, circadian-locomotor-output-cycles-kaput; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

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Fig. 3. CD4+ T-cell composition and plasma cortisol and thyroid-stimulating hormone in HIV-infected individuals on suppressive ART.

(a) CD4+ T-cell subset proportions in participants are shown for n = 28, 27 and 29 at B1, B2 and B3, respectively. The median and interquartile range are shown and comparisons are made with Wilcoxon matched pairs signed rank tests. (b) Plasma cortisol and (c) TSH in participants are shown for n = 27 at B1 and 30 at B2 and B3. The mean and standard deviation are shown and comparisons are made with paired t-tests. The color of the symbol denotes the preintervention time-point. These were prior to enrolment [screening (B1; black)], immediately before the first dose of an intervention, here being disulfiram (B3; red), and a time-point between (B2; grey). TSH, thyroid stimulating hormone.

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Fig. 4. The circadian transcription factors circadian-locomotor-output-cycles-kaput and brain-and-muscle-ARNT-like-1 upregulate HIV long-terminal repeat activity.

(a) Raw luciferase activity in 293T cells stably transfected with an HIV-LTR (HXB2)-luciferase reporter and then co-transfected with CLOCK, BMAL1, CLOCK and BMAL1 or Tat. (b) Fold change in luciferase activity. Comparisons are made to the HIV-LTR alone. (c) Schematic of the HIV LTR highlighting the position of E-box elements. (d) The effect of E-box mutations on upregulation of HIV LTR luciferase activity following co-transfection of CLOCK/BMAL-1. Fold change in luciferase activity of the mutated LTRs in the presence of CLOCK and BMAL1 compared with baseline expression. Box plots are shown, which demonstrate the median, 25th and 75th percentiles (box) and minimum and maximum values (whiskers), n = 13 (a and b) and n = 5 (d) experiments are shown. Comparisons were made using a linear regression analysis. *P < 0.05, **P < 0.01, ***P < 0.001. BMAL1, brain-and-muscle-ARNT-like-1; CLOCK, circadian-locomotor-output-cycles-kaput; WT, wild type.

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Fig. 5. Proposed model for interaction of visit, time and circadian genes in HIV transcription on antiretroviral therapy.

Effects of visit alone on CA-US HIV RNA remains unexplained but could potentially be secondary to stress. The CLOCK–BMAL-1 heterodimer binds to a six-nucleotide motif, the E-box [14,15], to mediate transcription. HIV-1 is known to encode multiple E-boxes in the LTR [16], and therefore changes in HIV transcription on ART, may plausibly be mediated directly through CLOCK–BMAL-1. BMAL1, brain-and-muscle-ARNT-like-1; CA-US, cell-associated unspliced; CLOCK, circadian-locomotor-output-cycles-kaput.

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Reference

1. Chang CC, Naranbhai V, Stern J, Roche M, Dantanarayana A, Ke R, et al. Variation in cell-associated unspliced HIV RNA on antiretroviral therapy is associated with the circadian regulator brain-and-muscle-ARNT-like-1. AIDS 2018; 32:2119–2128.
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