Systems biology applications to study mechanisms of human immunodeficiency virus latency and reactivation

Abstract

Eradication of human immunodeficiency virus (HIV) in infected individuals is currently not possible because of the presence of the persistent cellular reservoir of latent infection. The identification of HIV latency biomarkers and a better understanding of the molecular mechanisms contributing to regulation of HIV expression might provide essential tools to eliminate these latently infected cells. This review aims at summarizing gene expression profiling and systems biology applications to studies of HIV latency and eradication. Studies comparing gene expression in latently infected and uninfected cells identify candidate latency biomarkers and novel mechanisms of latency control. Studies that profiled gene expression changes induced by existing latency reversing agents (LRAs) highlight uniting themes driving HIV reactivation and novel mechanisms that contribute to regulation of HIV expression by different LRAs. Among the reviewed gene expression studies, the common approaches included identification of differentially expressed genes and gene functional category assessment. Integration of transcriptomic data with other biological data types is presently scarce, and the field would benefit from increased adoption of these methods in future studies. In addition, designing prospective studies that use the same methods of data acquisition and statistical analyses will facilitate a more reliable identification of latency biomarkers using different model systems and the comparison of the effects of different LRAs on host factors with a role in HIV reactivation. The results from such studies would have the potential to significantly impact the process by which candidate drugs are selected and combined for future evaluations and advancement to clinical trials.

Keywords: Gene expression; Microarrays; RNA-Seq; Systems biology; Human immunodeficiency virus; Viral latency; Disease eradication; Biomarkers; Molecular mechanisms; Latency reversing agents

Core tip: Gene expression profiling and systems biology methods are reviewed with respect to their possible application in the field of human immunodeficiency virus (HIV) research. Studies profiling gene expression in latently infected and uninfected cells are summarized to illustrate application of these methods to identification of latency biomarkers and the molecular mechanisms contributing to regulation of HIV expression. Studies that measure changes in host and HIV gene expression upon treatment with latency reversing agents (LRAs) highlight uniting themes driving HIV reactivation and identify novel mechanisms of action of LRAs. The field will further benefit from increased adoption of systems biology methods in future studies.