Disruption of LEDGF/p75-directed integration derepresses antisensetranscription of the HIV-1 genome
Tedbury, P. R.; Mahboubi, D.; Puray-Chavez, M.; Shah, R.; Ukah, O. B.; Wahoski, C. C.; Fadel, H. J.; Poeschla, E. M.; Gao, X.; McFadden, W. M.; Gaitanidou, M.; Kesesidis, N.; Kirby, K. A.; Vanderford, T. H.; Kvaratskhelia, M.; Achuthan, V.; Behrens, R. T.; Engelman, A. N.; Sarafianos, S. G.
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AbstractDisruption 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.
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