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.

doi:10.1101/2024.12.06.627169

bioRxiv · 10.1101/2024.12.06.627169

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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Abstract

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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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.. 2024-12-06. Disruption of LEDGF/p75-directed integration derepresses antisensetranscription of the HIV-1 genome. https://doi.org/10.1101/2024.12.06.627169

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