1. Disruption of LEDGF/p75-directed integration derepresses antisense transcription of the HIV-1 genome.
- Author
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Tedbury PR, Mahboubi D, Puray-Chavez M, Shah R, Ukah OB, Wahoski CC, Fadel HJ, Poeschla EM, Gao X, McFadden WM, Gaitanidou M, Kesesidis N, Kirby KA, Vanderford TH, Kvaratskhelia M, Achuthan V, Behrens RT, Engelman AN, and Sarafianos SG
- Abstract
Disruption of HIV-1 Integrase (IN) interactions with the host-factor Lens Epithelium-Derived Growth Factor (LEDGF)/p75 leads to decreased, random integration, increased latent infection, and described here, accumulation of HIV-1 antisense RNA (asRNA). asRNA increase was observed following interruptions of IN-LEDGF/p75 interactions either through pharmacologic perturbations of IN-LEDGF/p75 by treatment with allosteric HIV-1 integrase inhibitors (ALLINIs) or in cell lines with LEDGF genetic knockout. Additionally, by impairing Tat-dependent HIV transcription, asRNA abundance markedly increases. Illumina sequencing characterization of asRNA transcripts in primary T cells infected in the presence of ALLINIs showed that most initiate from within the HIV-1. Overall, loss of IN-LEDGF/p75 interactions increase asRNA abundance. Understanding the relationship between ALLINIs, integration sites, asRNA, and latency could aid in future therapeutic strategies.
- Published
- 2024
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