There is intense interest in developing safe and scalable curative interventions for Berlin patient has paved the way to identify therapeutic interventions that can lead to eradication of HIV. This goal can only be achieved by identifying the cellular localization of the HIV reservoir, the molecular mechanisms that result in the establishment and maintenance of latent infection and host determinants that dictate who might or might not respond to curative interventions. We have used an unbiased system biology approach to identify signal transduction pathways and transcriptional nodes that can predict the size of the HIV reservoir—as estimated by integrated HIV DNA levels—in a large cohort of long-term antiretroviral-treated adults. We show that distinct intracellular pathways associated with cell metabolism, activation and differentiation predict the estimated size of the reservoir. We found that upregulation of TGF-beta was associated with higher reservoir size, and validated the importance of the TGF-beta pathway in vitro using a primary T cell model of HIV latency. Finally we have shown that a specific subgroup of subjects who fail to reconstitute their immune system after ART (immune non-responders) have significantly higher levels of HIV replication competent latent HIV . We show using integrated OMICs approaches that the balance between FOXO3A and IRF-7 is a correlate of immune reconstitution and the size of the reservoir. System biology approaches have proven an essential tool in providing highly relevant clues that could lead to the identification of novel curative interventions. This work was funded by grants from the NIH U19 AI096109, Merck Research Laboratories, and the Fasenmayer Foundation.
Khader Ghneim, Jessica Brehm ,Aarthi Talla , Slim Fourati, Deanna Kulpa Nicolas Chomont ,Daria Hazuda , Steve Deeks and Michael Lederman. Case Western Research University, Merck Research Laboratories, Universite de Montreal , VGTI Florida and University of California, San Francisco