Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 225, Issue 10, Pages 1721-1730Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiab533
Keywords
circadian rhythm; estradiol; HIV latency; HIV RNA; HIV transcription
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Funding
- National Institutes of Health Delaney AIDS Research Enterprise (DARE) Collaboratory [U19 A1096109]
- National Institute for Mental Health
- National Health and Medical Research Council (NHMRC) of Australia [1149990, 1135851]
- National Health and Medical Research Council of Australia [1135851] Funding Source: NHMRC
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This study found that cell-associated unspliced HIV RNA in people with HIV on antiretroviral therapy varies temporally with a circadian rhythm, while HIV DNA remains constant. Circulating estradiol is highly predictive of HIV RNA variation.
Background Circadian transcription factors that regulate cell-autonomous circadian clocks can also increase human immunodeficiency virus (HIV) transcription in vitro. We aimed to determine whether circadian variation in HIV transcription exists in people with HIV (PWH) on antiretroviral therapy (ART). Methods We performed a prospective observational study of male PWH on ART, sampling blood every 4 hours for 24 hours. Using quantitative polymerase chain reaction, we quantified expression of circadian-associated genes, HIV deoxyribonucleic acid (DNA), and cell-associated unspliced (CA-US) ribonucleic acid (RNA) in peripheral blood CD4+ T cells. Plasma sex hormones were quantified alongside plasma and salivary cortisol. The primary outcome was to identify temporal variations in CA-US HIV RNA using a linear mixed-effect regression framework and maximum likelihood estimation. Results Salivary and plasma cortisol, and circadian genes including Clock, Bmal1, and Per3, varied with a circadian rhythm. Cell-associated unspliced HIV RNA and the ratio of CA-US HIV RNA/DNA in CD4+ T cells also demonstrated circadian variations, with no variation in HIV DNA. Circulating estradiol was highly predictive of CA-US HIV RNA variation in vivo. Conclusions Cell-associated unspliced HIV RNA in PWH on ART varies temporally with a circadian rhythm. These findings have implications for the design of clinical trials and biomarkers to assess HIV cure interventions. Despite suppressive antiretroviral therapy, males with HIV display a circadian cycling in cell-associated HIV RNA, having implications on the design of cure trials such as sampling and intervention times. Circadian cycles offer a novel target for latency reversal.
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