# The circadian rhythm as a lentiviral vector restriction factor

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $770,756

## Abstract

Abstract:
Circadian rhythm (CR) defines the daily oscillation in gene expression that controls major physiologic pathways
in eukaryotic cells in vivo and in vitro. These biological processes include DNA repair activity, innate and adaptive
immune functions, inflammation, and metabolic pathways. CRs are premised on autonomous peripheral
oscillatory cores, which exist in most organs as well as in cultured cells. In vivo, a central master clock located
in the suprachiasmatic nucleus (SCN) synchronizes the peripheral oscillatory cores via the sympathetic nervous
system and neuroendocrine agents such as melatonin (Mel). Peripheral organs are also entrained by various
metabolic/hormonal and physical inputs (e.g. Dexamethasone, food intake, temperature). However, only the
master SCN core receives light inputs via the retinal hypothalamic tract. All oscillatory cores are based on similar
positive/negative transcriptional/translational feedback loops. Recent studies demonstrated major CR effects on
the course of viral infections in murine models. Altering the time of viral application and knocking out genes
encoding oscillatory core proteins enhanced viral infection by up to 10-fold. To date, CR effects on the efficacy
of Lentiviral vector (LVV) transduction have not been studied. We hypothesize that the CR is a high-level
restriction factor to viral-vector transduction. We propose three specific aims to test this hypothesis. In aim 1, we
will characterize the effects of normal and disrupted CR behavior on hepatic transduction efficiency by LVVs.
We will employ three mouse strains showing distinct circadian behavior and melatonin (Mel) production, including
C3H(Mel+), C57B6 (Mel-), and BMAL1 (oscillatory core protein)-deficient mice. The effects of time of vector
administration, and exposure to either Mel or the Mel- receptor antagonist on hepatic transduction will be
determined. The effects of altered CR behavior patterns on vector transduction will be determined a) following
CR disruption by an acute opioid withdrawal protocol in C57B6 and C3H mice, and b) by gene delivery to naïve
C57B6 and C3H mice following disruption of the normal day-sleep time period. In aim 2, We will test the
hypothesis that normal and disrupted CRs affect LVV transduction efficiency in human and mouse cells in vitro.
Specifically, we will quantify the effects of dexamethasone entrainment on LVV transduction of human and
mouse cells comprising either normal or mutant BMAL1 gene. In aim 3, We will employ an F2 cross between
the CC036 and CC057 mouse strains to determine the existence of a genetic association between the efficiency
of LVV mediated hepatic gene delivery and CR patterns and will identify genetic loci contributing to the above
host and LVV characteristics.

## Key facts

- **NIH application ID:** 9943715
- **Project number:** 1R01HL155986-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** TAL KAFRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $770,756
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9943715

## Citation

> US National Institutes of Health, RePORTER application 9943715, The circadian rhythm as a lentiviral vector restriction factor (1R01HL155986-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9943715. Licensed CC0.

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