Disruption of LEDGF/p75-directed integration derepresses antisensetranscription of the HIV-1 genome

Philip R. Tedbury; Darius Mahboubi; Maritza Puray‐Chavez; Raven Shah; Obiaara B. Ukah; Claudia C. Wahoski; Hind J. Fadel; Eric M. Poeschla; Xinlin Gao; William M. McFadden; Maria Gaitanidou; Nikolaos Kesesidis; Karen A. Kirby; Thomas H. Vanderford; Mamuka Kvaratskhelia; Vasudevan Achuthan; Ryan T. Behrens; Alan Engelman; Stefan G. Sarafianos

doi:10.1101/2024.12.06.627169

MicrobiologybioRxivDec 6, 2024

Preprint

Disruption of LEDGF/p75-directed integration derepresses antisensetranscription of the HIV-1 genome

Philip R. Tedbury iD, Darius Mahboubi iD, Maritza Puray‐Chavez iD, Raven Shah iD, Obiaara B. Ukah, Claudia C. Wahoski iD, Hind J. Fadel, Eric M. Poeschla iD, Xinlin Gao iD, William M. McFadden iD, Maria Gaitanidou iD, Nikolaos Kesesidis iD, Karen A. Kirby iD, Thomas H. Vanderford iD, Mamuka Kvaratskhelia iD, Vasudevan Achuthan, Ryan T. Behrens iD, Alan Engelman iD, Stefan G. Sarafianos iD

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.

PDF DOI