Altering Stochastic Noise in Gene Expression for HIV Therapy

Abstract

HIV's ability to enter a transcriptionally dormant state and establish a reservoir of latently infected cells is the major barrier to eradicating HIV from infected patients. Significant efforts are aimed at reactivating latent HIV and purging the reservoir through targeting of molecular mechanisms implicated in the establishment of latency. These efforts to perturb the latent reservoir have faced substantial challenges. Our previous studies implicated stochastic noise (i.e. fluctuations) in an HIV transcriptional positive-feedback circuit as crucial for the establishment of HIV latency and predicted that perturbing noise would alter HIV latency (Weinberger et al. Cell 2005; Dar et al. PNAS 2012). Here, we demonstrate that manipulation of stochastic noise in HIV gene expression radically perturbs HIV latency. Screening a library of small-molecule drug compounds identified over 50 compounds that modulate noise in the HIV promoter without changing the promoter's mean expression level. Strikingly, the noise-modulating compounds synergize with conventional transcriptional activators and surpass current best-in-class reactivation cocktails, while maintaining greater cell viability. Thus, noise-modulating compounds may present an approach to perturb the stability of the latent state. More generally, stochastic noise may represent a new unexplored axis for drug discovery that allows enhanced control over cell-fate specification decisions, metastasis, and pathogen persistence phenotypes.