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Cell-associated HIV RNA has a Circadian Cycle in Males Living with HIV on Antiretroviral Therapy. BACKGROUND: Circadian transcription factors that regulate cell-autonomous circadian clocks can also increase HIV transcription in vitro. We aimed to determine if circadian variation in HIV transcription exists in people living with HIV (PLHIV) on antiretroviral therapy (ART). METHODS: We performed a prospective observational study of male PLHIV on ART, sampling blood every four hours for 24 hours. Using qPCR, we quantified expression of circadian associated genes, HIV DNA and cell-associated unspliced (CA-US) 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. CA-US HIV RNA and the ratio of CA-US HIV RNA-to-DNA in CD4+ T-cells also demonstrated circadian variations, with no variation in HIV DNA. Circulating oestradiol was highly predictive of CA-US HIV RNA variation in vivo. CONCLUSION: CA-US HIV RNA in PLHIV 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.