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

Table 1 Methods of gene expression profiling and systems biology and their applications in the field of human immunodeficiency virus latency and eradication

Method	Applications to discovery of latency biomarkers and mechanisms of regulation of HIV expression	Applications to studying the LRA mechanisms of action and evaluating combination therapies
Differential gene expression	Identification of latency biomarkers	Identification of genes responsive to LRA treatment
GO term/pathway enrichment	(1) Focusing study efforts upon gene groups of interest (e.g., membrane proteins as biomarkers)	(1) Elucidation of mechanisms of action of LRAs
	(2) Identification of the mechanisms behind gene expression alterations	(2) Selection of gene targets for combination therapy based on gene function in enriched pathway
	(3) Delineating the molecular mechanisms contributing to latency control
Network-based analysis	Identification of major regulators involved in HIV latency control, which may be only slightly dysregulated but significantly affect downstream molecules and pathways	(1) Elucidation of mechanisms of action of LRAs;
		(2) Prioritization of targets for combination therapies based upon type of connectivity (include if it regulates HIV-related processes; exclude if it regulates general intracellular processes)
Consolidating gene expression with other biological data (proteome, integration sites, chromatin features, etc.)	(1) Identification of latency biomarkers with transient RNA, but stable protein expression;	(1) Identification of post-transcriptional mechanisms of action of LRAs;
	(2) Identification of mechanisms of latency control by correlating chromatin features to gene expression	(2) Assessment of chromatin features of genes and HIV integration sites responsive to LRA treatment
HIV expression and transcript type	Potential biomarker of latency	Assessment of the effectiveness of LRAs for HIV reactivation

LRA: Latency reversing agent; GO: Gene ontology; HIV: Human immunodeficiency virus.